Family of aryl, heteroaryl, o-aryl and o-heteroaryl carbasugars

ABSTRACT

The present invention relates to a compound of the following formula (I): as well as its process of preparation, pharmaceutical and cosmetics composition comprising it and use thereof, notably as an inhibitor of the sodium-dependent glucose co-transporter, such as SGLT1, SGLT2 and SGLT3, in particular in the treatment or prevention of diabetes, and more particularly type-II diabetes, diabetes-related complications, such as arthritis of the lower extremities, cardiac infarction, renal insufficiency, neuropathy or blindness, hyperglycemia, hyperinsulinemia, obesity, hypertriglyceridemia, X syndrome and arteriosclerosis, as well as for its use as an anticancer, anti-infective, anti-viral, anti-thrombotic or anti-inflammatory drug, or for lightening, bleaching, depigmenting the skin, removing blemishes from the skin, particularly age spots and freckles, or preventing pigmentation of the skin.

This invention relates to a family of fluorinated aryl, heteroaryl,O-aryl and O-heteroaryl glycoside compounds, the process for theirpreparation, as well as the application of same in the pharmaceutical orcosmetic fields, in particular for the treatment or prevention ofdiabetes and obesity, and as depigmenting or lightening agent.

Sugars and the derivatives thereof constitute one of the most commonclasses of compounds in nature. Based on their chemical structures, theyexhibit various physico-chemical properties and can play a key role in awide variety of biological processes.

In recent years, there has been a growing interest in discovering newglycosides having advantageous properties in terms of improved efficacy,selectivity and stability.

Found among these compounds, in particular, are aryl glycosides orphenol glycosides having applications in the field of cosmetics or inthe treatment or prevention of diseases such as diabetes, obesity,cancer, inflammatory diseases, auto-immune diseases, infections,thromboses, and with regard to numerous other therapeutic fields. Bytheir biological properties and their structure, these compoundsinterest numerous research teams.

Phlorizin may be cited in particular, as a molecule known for itsinhibiting activity with regard to sodium-dependent glucoseco-transporters (SGLT) (Journal of Clinical Investigation, vol. 79, p.1510, (1987); ibid., vol. 80, p. 1037 (1987); ibid., vol. 87, p. 561(1991); J. of Med. Chem., vol. 42, p. 5311 (1999); British Journal ofPharmacology, vol. 132, p. 578, (2001)).

Inhibitors of sodium-dependent glucose co-transporters (SGLT), found inparticular in the intestines and kidney, are potentially usable fortreating diabetes, and more specifically type-II diabetes, but also forhyperglycemia, hyperinsulinemia, obesity, hypertriglyceridemia, syndromeX (also known by the name of metabolic syndrome, J. of Clin. Endocrinol.Metabol., 82, 727-734 (1997)), diabetes-related complications or elseatherosclerosis. As a matter of fact, it is known that hyperglycemiaparticipates in the onset and evolution of diabetes and leads to areduction in the secretion of insulin and a reduction in insulinsensitivity, which results in an increase in the glucose level, therebyexacerbating diabetes. The treatment of hyperglycemia can thus beconsidered as a mean to treat diabetes.

Such being the case, one of the methods for treating hyperglycemia is topromote the excretion of excess of glucose directly into the urine,e.g., by inhibiting the sodium-dependent glucose co-transporter in theproximal tubules of the kidneys, the effect of which is to inhibit there-absorption of glucose and to thereby promote the excretion thereofinto the urine, leading thus to a reduction in the blood-sugar level.

At present, a large number of drugs exist, which can be used fortreating diabetes, such as biguanides, sulfonylureas, insulinresistance-improving agents, and inhibitors of α-glycosidases. However,these compounds have numerous side effects, thereby increasing the needfor new drugs.

Therefore, the invention provides new compounds, which are useful, inparticular, for the treatment or prevention of diabetes and obesity.

These compounds are CF₂-analogues of aryl, heteroaryl, O-aryl,O-heteroaryl glycosides, wherein the intracyclic glycosidic oxygen isreplaced by a carbon atom, carrying two fluorine atoms. These compoundswill have the distinctive feature of being stable analogues of O-aryland O-heteroaryl glycosides, when confronted with enzymatic degradationprocesses, in particular via glycosidase-type enzymes. Moreover,difluorinated carbon is a good mimic of the oxygen atom.

Stable aryl-glycoside analogues, wherein it is the anomeric oxygen whichis replaced by a carbon atom carrying two fluorine atoms, are describedin the patent application WO 2009/121 939.

The synthesis of O-aryl glycosides wherein the intracyclic or anomericoxygen is replaced by a carbon atom, carrying two fluorine atoms isdescribed in the patent applications WO 2005/044 256. The synthesis ofthe following compound is notably described:

O-aryl and aryl analogues wherein the endocyclic oxygen is replaced by acarbon atom carrying two halogen atoms have also been reported in WO2009/076 550 but have not been exemplified.

The inventors have thus developed new synthetic approaches enablingaccess to new aryl, heteroaryl, O-aryl and O-hetero-aryl compounds,useful as SGLT inhibitors, in particular for the treatment or preventionof diabetes and obesity, and useful as Tyrosinase inhibitors, notablyfor cosmetic applications and especially as depigmenting or lightneningagents and also as antioxydants.

Therefore, the present invention relates to a compound having thefollowing formula (I):

or a pharmaceutically or cosmetically acceptable salt thereof, atautomer, a stereoisomer or a mixture of stereoisomers in anyproportion, in particular a mixture of enantiomers, and particularly aracemate mixture,

wherein:

-   -   n, m and p represent, independently from one another, 0 or 1,    -   R represents a hydrogen or a fluorine atom or a CH₃, CH₂F,        CH₂OH, CH₂OSiR^(a)R^(b)R^(c), CH₂OR¹¹, CH₂OCOR¹¹, CH₂OCO₂R¹¹,        CH₂OCONR¹²R¹³, CH₂OP(O)(OR¹⁴)₂ or CH₂OSO₃R¹⁴ group,    -   R₁ and R₂ represent, independently from one another, a fluorine        atom or an OH, OSiR^(d)R^(e)R^(f), OR¹⁵, OCOR¹⁵, OCO₂R¹⁵ or        OCONR¹⁶R¹⁷ group,    -   R₃ represents a hydrogen or fluorine atom or an OH,        OSiR^(g)R^(h)R^(i), OR¹⁸, OCOR¹⁸, OCO₂R¹⁸, OCONR¹⁹R²⁰, NR¹⁹R²⁰        or NR¹⁹COR¹⁸ group,    -   R₄ represents a hydrogen atom when n=1, and R₄ represents a        hydrogen atom, an halogen atom or an OH, OSiR^(j)R^(k)R^(l),        OR²¹, OCOR²¹, OCO₂R²¹, or OCONR²²R²³ group when n=0,

or R and R₁, together with the carbon atoms carrying them, form a cyclicacetal having the following formula:

and/or (R₁ and R₂), (R₂ and R₃), and/or (R₃ and R₄), together with thecarbon atoms carrying them, form a cyclic acetal having the followingformula:

and

-   -   X₁ represents a hydrogen atom, an halogen atom, a CN, OH, SO₂,        SiR^(m)R^(n)R^(o), (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,        (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, OR²⁴, COR²⁴, OCOR²⁴,        CO₂R²⁴, NR²⁵R²⁶, NR²⁵COR²⁴, CONR²⁵R²⁶, SR²⁴, SO₂R²⁴, CSR²⁴ or        OSO₃R²⁴ group, and    -   U, V and W represent, independently from one another, a phenyl,        pyrazolyl, N—(C₁-C₆)alkyl-pyrazolyl, or thienyl ring,    -   the said ring being optionally substituted with one or more        substituents selected from the group consisting of an halogen        atom, a CN, OH, SO₂, SiR^(m)R^(n)R^(o), (C₁-C₆)-alkyl,        (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, OR²⁴,        COR²⁴, OCOR²⁴, CO₂R²⁴, NR²⁵R²⁶, NR²⁵COR²⁴, CONR²⁵R²⁶, SR²⁴,        SO₂R²⁴, and OSO₃R²⁴ group,    -   with:    -   R¹¹, R¹⁵, R¹⁸, R²¹ and R²⁴ representing, independently from one        another, a (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,        (C₃-C₇)-cycloalkyl, 5 to 7 ring-membered heterocycloalkyl, aryl,        aryl-(C₁-C₆)-alkyl or (C₁-C₆)-alkyl-aryl group, this group being        possibly substituted by one or more groups chosen among an        halogen atom, an OH, COOH and CHO group,    -   R¹², R¹³, R¹⁶, R¹⁷, R¹⁹, R²⁰, R²², R²³, R²⁵ and R²⁶        representing, independently from one another, a hydrogen atom or        a (C₁-C₆)-alkyl or aryl-(C₁-C₆)-alkyl group,    -   R¹⁴ representing a hydrogen atom or a (C₁-C₆)-alkyl group,    -   R^(a) to R^(o) representing, independently from one another, a        (C₁-C₆)-alkyl, aryl or aryl-(C₁-C₆)-alkyl group, and    -   R^(p) to R^(s) representing, independently from one another, a        hydrogen atom, a (C₁-C₆)-alkyl group, aryl or aryl-(C₁-C₆)-alkyl        group.

In this invention, “pharmaceutically or cosmetically acceptable” isunderstood to mean what is useful in the preparation of a pharmaceuticalor cosmetic composition which is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and which is acceptable forveterinary and human pharmaceutical use, as well as cosmetic use.

In this invention, “pharmaceutically or cosmetically acceptable salts”of a compound, is understood to designate salts which arepharmaceutically or cosmetically acceptable, as defined herein, andwhich possess the desired pharmacological activity of the parentcompound. Such salts include:

-   -   (1) hydrates and solvates, such as (S)-propylene glycol solvate,    -   (2) acid addition salts formed with inorganic acids such as        hydrochloric acid, bromhydric acid, sulphuric acid, nitric acid,        phosphoric acid or the like; or formed with organic acids such        as acetic acid, benzenesulfonic acid, benzoic acid,        camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric        acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic        acid, hydroxynaphtoic acid, 2-hydroxyethanesulfonic acid, lactic        acid, maleic acid, malic acid, mandelic acid, methanesulfonic        acid, muconic acid, 2-naphtalenesulfonic acid, propionic acid,        salicylic acid, succinic acid, dibenzoyl-L-tartaric acid,        tartaric acid, p-toluenesulfonic acid, trimethylacetic acid,        trifluoroacetic acid and the like; and    -   (3) salts formed when an acid proton present in the parent        compound is either replaced by a metal ion, e.g., an alkali        metal ion (e.g., Na⁺, K⁺ or Li⁺), an alkaline-earth metal ion        (like Ca²⁺ or Mg²⁺) or an aluminium ion; or coordinates with an        organic or inorganic base. Acceptable organic bases include        diethanolamine, ethanolamine, N-methylglucamine,        triethanolamine, tromethamine and the like. Acceptable inorganic        bases include aluminium hydroxide, calcium hydroxide, potassium        hydroxide, sodium carbonate and sodium hydroxide.

In this invention, “tautomer” is understood to designate an isomerobtained by prototropy, i.e. migration of a hydrogen atom and change oflocalisation of a double bond. The different tautomers of a compound aregenerally interconvertible and present in equilibrium in solution, invarious proportions which can depend on the solvent used, on thetemperature or on the pH.

In this invention, “stereoisomers” mean isomers having the samemolecular formula and sequence of bonded atoms but which differ in thethree-dimensional orientations of their atoms in space. They designatethus E/Z isomers, diastereoisomers and enantiomers. E/Z isomers arecompounds having a double bond, the substituents present on this doublebond being not on the same side of the double bond. Stereoisomers whichare not mirror images of one another are thus designated as“diastereoisomers”, and stereoisomers which are non-superimposablemirror images are designated as “enantiomers”.

Notably, the sugar moiety of the compounds of the invention can belongto the D or L series, and preferably to the D series.

A carbon atom bound to four non-identical substituents is called a“chiral centre”.

An equimolar mixture of two enantiomers is called a racemate mixture.

Within the meaning of this invention, “halogen” is understood to mean anatom of fluorine, bromine, chlorine or iodine.

Within the meaning of this invention, “(C₁-C₆)-alkyl” group isunderstood to mean a saturated, linear or branched hydrocarbon chaincomprising from 1 to 6 carbon atoms, in particular the methyl, ethyl,n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,n-pentyl, n-hexyl groups.

Within the meaning of this invention, “(C₂-C₆)-alkenyl” group isunderstood to mean a linear or branched hydrocarbon chain comprising atleast one double bond and comprising from 2 to 6 carbon atoms, e.g.,such as an ethenyl (vinyl) or propenyl group.

Within the meaning of the invention, “(C₂-C₆)-alkynyl” group isunderstood to mean a linear or branched hydrocarbon chain comprising atleast one triple bond and comprising from 2 to 6 carbon atoms, e.g.,such as an ethynyl or propynyl group.

Within the meaning of this invention, “(C₃-C₇)-cycloalkyl” group isunderstood to mean a saturated hydrocarbon ring comprising from 3 to 7,advantageously from 5 to 7, carbon atoms, in particular the cyclohexyl,cyclopentyl or cycloheptyl group.

Within the meaning of this invention, “5 to 7 ring-memberedheterocycloalkyl” group is understood to mean a saturated hydrocarbonring having 5 to 7 members and containing one or more, advantageouslyone or two, heteroatoms in place of the carbon atoms, e.g., such assulphur, nitrogen or oxygen atoms, e.g., such as the tetrahydrofuranyl,piperidinyl, pyrrolidinyl, tetrahydropyranyl, 1,3-dioxolanyl group.

Within the meaning of this invention, “aryl” group is understood to meana hydrocarbon aromatic group preferably comprising from 5 to 10 carbonatoms and including one or more fused rings, e.g., such as a phenyl ornaphtyl group. This is advantageously phenyl.

Within the meaning of this invention, “aryl-(C₁-C₆)-alkyl” group isunderstood to mean any aryl group as defined above, which is bound tothe molecule by means of a (C₁-C₆)-alkyl group as defined above. Inparticular, a group such as this can be a benzyl group.

Within the meaning of this invention, “(C₁-C₆)-alkyl-aryl” group isunderstood to mean a (C₁-C₆)-alkyl group as defined above, which isbound to the molecule by means of an aryl group as defined above. Inparticular, a group such as this can be a methylphenyl group.

Within the meaning of this invention, “N—(C₁-C₆)alkyl-pyrazolyl” groupis a group of the following formula, wherein X represents a (C₁-C₆)alkylgroup as defined above:

this group being bound to the rest of the molecule by two of the carbonatoms of the pyrazolyl moiety.

The compounds of the invention are advantageously based on the followingformulas (Ia), (Ib) and (Ic), and in particular (Ia) and (Ic):

with R, R₁, R₂, R₃, R₄, X₁, U, V, W, n, m and p as defined above.

Advantageously, R₁ and R₂ represent, independently from one another, afluorine atom or an OH, OSiR^(d)R^(e)R^(f), OR¹⁵, OCOR¹⁵, OCO₂R¹⁵ orOCONR¹⁶R¹⁷ group and R₃ represents a fluorine atom or an OH,OSiR^(g)R^(h)R^(i), OR¹⁸, OCOR¹⁸, OCO₂R¹⁸ or OCONR¹⁹R²⁰ group.

More advantageously, R₁ and R₂ represent, independently from oneanother, an OH, OR¹⁵ or OCOR¹⁵ group and R₃ represents an OH, OR¹⁸ orOCOR¹⁸ group.

Even more advantageously, R₁, R₂ and R₃ may be chosen, independentlyfrom one another, among an OH, —O—(C₁-C₆)-alkyl, —O-aryl,—O—(C₁-C₆)-alkyl-aryl and —OCO—(C₁-C₆)-alkyl group.

In particular, R₁, R₂ and R₃ may be chosen, independently from oneanother, among an OH, OSiMe₃ and benzyloxy (OBn) group, and preferablyamong OH and OBn.

According to a particular embodiment, R₁, R₂ and R₃ are identical.

According to another particular embodiment, R₁, R₂ and R₃ are identicaland represent each an OH group and R represents a CH₂OH group.

R advantageously represents a hydrogen atom or a CH₃, CH₂OH, CH₂OR¹¹,CH₂OSiR^(a)R^(b)R^(c), CH₂OCOR¹¹, CH₂OP(O)(OH)₂ or CH₂OSO₃H group, andin particular a hydrogen atom or a CH₃, CH₂OH, CH₂OR¹¹, CH₂OCOR¹¹,CH₂OP(O)(OH)₂ or CH₂OSO₃H group,

with R^(a), R^(b), R^(c) and R¹¹ as defined above, and with CH₂OR¹¹advantageously representing a —CH₂O—(C₁-C₆)-alkyl, —CH₂O-aryl and—CH₂O—(C₁-C₆)-alkyl-aryl, and CH₂OCOR¹¹ group, more advantageouslyrepresenting a —CH₂OCO—(C₁-C₆)-alkyl group.

Even more advantageously, R represents a CH₂OH, CH₂OSiR^(a)R^(b)R^(c),CH₂OR¹¹ or CH₂OCOR¹¹ group, and more advantageously a CH₂OH, CH₂OR¹¹ orCH₂OCOR¹¹ group, with R^(a), R^(b), R^(c) and R¹¹ as defined above.

Yet even more advantageously, R represents a CH₂OH, —CH₂O—(C₁-C₆)-alkyl,—CH₂O-aryl, —CH₂O—(C₁-C₆)-alkyl-aryl and —CH₂OCO—(C₁-C₆)-alkyl group.

In particular, R can represent a CH₂OH, CH₂OSiMe₃ or CH₂OBn group, andpreferably a CH₂OH or CH₂OBn group.

In the same way, R₄ may advantageously represent a hydrogen or halogenatom or an OH or OR²⁴ group, and in particular a hydrogen atom or an OHor OR²⁴ group, with R²⁴ as defined above.

Yet even more advantageously, R₄ may represent a hydrogen or halogenatom or an OH, —O—(C₁-C₆)-alkyl, —O-aryl and —O—(C₁-C₆)-alkyl-arylgroup, and in particular, a hydrogen atom or an OH, —O—(C₁-C₆)-alkyl,—O-aryl and —O—(C₁-C₆)-alkyl-aryl group.

In particular, R₄ can represent a hydrogen or halogen (such as Br, Cl,F) atom or an OH group, and advantageously, a hydrogen atom or an OHgroup, and notably a hydrogen atom.

Preferably, R₄=H when n=1 and R₄=H or OH when n=0.

Advantageously, X₁ is selected from the group consisting of a hydrogenatom, an halogen atom, a OH, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, OR²⁴, COR²⁴, OCOR²⁴, CO₂R²⁴,NR²⁵R²⁶, NR²⁵COR²⁴ and CONR²⁵R²⁶ group; more advantageously from thegroup consisting of a hydrogen atom, an halogen atom, a OH,(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,OR²⁴, COR²⁴, OCOR²⁴ and CO₂R²⁴ group; even more advantageously from thegroup consisting of a hydrogen atom, an halogen atom, a OH,(C₁-C₆)-alkyl and OR²⁴ group.

Advantageously, U, V and W represent, independently from one another, aphenyl, pyrazolyl, N—(C₁-C₆)alkyl-pyrazolyl, or thienyl ring, the saidring being optionally substituted with one or more substituents selectedfrom the group consisting of an halogen atom, a OH, (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, OR²⁴, COR²⁴,OCOR²⁴, CO₂R²⁴, NR²⁵R²⁶, NR²⁵COR²⁴ and CONR²⁵R²⁶ group; moreadvantageously from the group consisting of an halogen atom, a OH,(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,OR²⁴, COR²⁴, OCOR²⁴ and CO₂R²⁴ group; even more advantageously from thegroup consisting of an halogen atom, a OH, (C₁-C₆)-alkyl and OR²⁴ group.

(1) In a first embodiment, n is 1.

In a first subclass of this embodiment, m=0 and U is an optionallysubstituted phenyl. The compounds according to the invention can thus berepresented by the following formula (I-1), and more particularly by thefollowing formulas (I-1a), (I-1b) and (I-1c), and in particular (I-1a)and (I-1c):

or a pharmaceutically or cosmetically acceptable salt thereof, atautomer, a stereoisomer or a mixture of stereoisomers in anyproportion, in particular a mixture of enantiomers, and particularly aracemate mixture,

wherein:

-   -   R, R₁, R₂, and R₃ are as defined above, and    -   X₁, X₂, X₃, X₄ and X₅ represent, independently from one another,        a hydrogen atom, an halogen atom, a CN, OH, SO₂,        SiR^(m)R^(n)R^(o), (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,        (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, OR²⁴, COR²⁴, OCOR²⁴,        CO₂R²⁴, NR²⁵R²⁶, NR²⁵COR²⁴, CONR²⁵R²⁶, SR²⁴, SO₂R²⁴, CSR²⁴ or        OSO₃R²⁴ group; advantageously from the group consisting of a        hydrogen atom, an halogen atom, a OH, (C₁-C₆)-alkyl,        (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, OR²⁴,        COR²⁴, OCOR²⁴, CO₂R²⁴, NR²⁵R²⁶, NR²⁵COR²⁴ and CONR²⁵R²⁶ group;        more advantageously from the group consisting of a hydrogen        atom, an halogen atom, a OH, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,        (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, OR²⁴, COR²⁴, OCOR²⁴ and        CO₂R²⁴ group; even more advantageously from the group consisting        of a hydrogen atom, an halogen atom, a OH, (C₁-C₆)-alkyl and        OR²⁴ group.

Examples within this first subclass include but are not limited to:

In a second subclass of this embodiment, m=1, p=0 and U and V represent,independently from one another, an optionally substituted phenyl. Thecompounds according to the invention can thus be represented by thefollowing formula (I-2), and more particularly by the following formulas(I-2a) and (I-2b), and in particular (I-2a):

or a pharmaceutically or cosmetically acceptable salt thereof, atautomer, a stereoisomer or a mixture of stereoisomers in anyproportion, in particular a mixture of enantiomers, and particularly aracemate mixture,

wherein:

-   -   R, R₁, R₂, and R₃ are as defined above, and    -   X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈ and X₉ represent, independently        from one another, a hydrogen atom, an halogen atom, a CN, OH,        SO₂, SiR^(m)R^(n)R^(o), (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,        (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, OR²⁴, COR²⁴, OCOR²⁴,        CO₂R²⁴, NR²⁵R²⁶, NR²⁵COR²⁴, CONR²⁵R²⁶, SR²⁴, SO₂R²⁴, CSR²⁴ or        OSO₃R²⁴ group; advantageously from the group consisting of a        hydrogen atom, an halogen atom, a OH, (C₁-C₆)-alkyl,        (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, OR²⁴,        COR²⁴, OCOR²⁴, CO₂R²⁴, NR²⁵R²⁶, NR²⁵COR²⁴ and CONR²⁵R²⁶ group;        more advantageously from the group consisting of a hydrogen        atom, an halogen atom, a OH, (C₁-C₆-alkyl, (C₂-C₆)-alkenyl,        (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, OR²⁴, COR²⁴, OCOR²⁴ and        CO₂R²⁴ group; even more advantageously from the group consisting        of a hydrogen atom, an halogen atom, a OH, (C₁-C₆)-alkyl and        OR²⁴ group.

Examples within this second subclass include but are not limited to:

In a third subclass of this embodiment, m=1, p=0, U is a pyrazolyl orN—(C₁-C₆)alkyl-pyrazolyl group and V is an optionally substitutedphenyl. The compounds according to the invention can thus be representedby the following formula (I-3), and more particularly by the followingformulas (I-3a) and (I-3b), and in particular (I-3a):

or a pharmaceutically or cosmetically acceptable salt thereof, atautomer, a stereoisomer or a mixture of stereoisomers in anyproportion, in particular a mixture of enantiomers, and particularly aracemate mixture,

wherein:

-   -   R, R₁, R₂, and R₃ are as defined above,    -   X₁, X₂, X₃, X₄, X₅ and X₆ represent, independently from one        another, a hydrogen atom, an halogen atom, a CN, OH, SO₂,        SiR^(m)R^(n)R^(o), (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,        (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, OR²⁴, COR²⁴, OCOR²⁴,        CO₂R²⁴, NR²⁵R²⁶, NR²⁵COR²⁴, CONR²⁵R²⁶, SR²⁴, SO₂R²⁴, CSR²⁴ or        OSO₃R²⁴ group; advantageously from the group consisting of a        hydrogen atom, an halogen atom, a OH, (C₁-C₆)-alkyl,        (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, OR²⁴,        COR²⁴, OCOR²⁴, CO₂R²⁴, NR²⁵R²⁶, NR²⁵COR²⁴ and CONR²⁵R²⁶ group;        more advantageously from the group consisting of a hydrogen        atom, an halogen atom, a OH, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,        (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, OR²⁴, COR²⁴, OCOR²⁴ and        CO₂R²⁴ group; even more advantageously from the group consisting        of a hydrogen atom, an halogen atom, a OH, (C₁-C₆)-alkyl and        OR²⁴ group, and    -   X represents a hydrogen atom or a (C₁-C₆)-alkyl group.

Examples within this third subclass include but are not limited to:

(2) In a second embodiment, n is 0.

In a first subclass of this embodiment, m=1, p=0 and U and V areindependently an optionally substituted phenyl. The compounds accordingto the invention can thus be represented by the following formula (I-4),and more particularly by the following formulas (I-4a) and (I-4b), andin particular (I-4a):

or a pharmaceutically or cosmetically acceptable salt thereof, atautomer, a stereoisomer or a mixture of stereoisomers in anyproportion, in particular a mixture of enantiomers, and particularly aracemate mixture,

wherein:

-   -   R, R₁, R₂, R₃ and R₄ are as defined above, and    -   X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈ and X₉ represent, independently        from one another, a hydrogen atom, an halogen atom, a CN, OH,        SO₂, SiR^(m)R^(n)R^(o), (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,        (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, OR²⁴, COR²⁴, OCOR²⁴,        CO₂R²⁴, NR²⁵R²⁶, NR²⁵COR²⁴, CONR²⁵R²⁶, SR²⁴, SO₂R²⁴, CSR²⁴ or        OSO₃R²⁴ group; advantageously from the group consisting of a        hydrogen atom, an halogen atom, a OH, (C₁-C₆)-alkyl,        (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, OR²⁴,        COR²⁴, OCOR²⁴, CO₂R²⁴, NR²⁵R²⁶, NR²⁵COR²⁴ and CONR²⁵R²⁶ group;        more advantageously from the group consisting of a hydrogen        atom, an halogen atom, a OH, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,        (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, OR²⁴, COR²⁴, OCOR²⁴ and        CO₂R²⁴ group; even more advantageously from the group consisting        of a hydrogen atom, an halogen atom, a OH, (C₁-C₆)-alkyl and        OR²⁴ group.

Examples within this first subclass include but are not limited to:

In a second subclass of this embodiment, m=1, p=1, U and W areindependently an optionally substituted phenyl and V is an optionallysubstituted thienyl. The compounds according to the invention can thusbe represented by the following formula (I-5), and more particularly bythe following formulas (I-5a) and (I-5b), and in particular (I-5a):

or a pharmaceutically or cosmetically acceptable salt thereof, atautomer, a stereoisomer or a mixture of stereoisomers in anyproportion, in particular a mixture of enantiomers, and particularly aracemate mixture,

wherein:

-   -   R, R₁, R₂, R₃ and R₄ are as defined above, and    -   X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀ and X₁₁ represent,        independently from one another, a hydrogen atom, an halogen        atom, a CN, OH, SO₂, SiR^(m)R^(n)R^(o), (C₁-C₆)-alkyl,        (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, OR²⁴,        COR²⁴, OCOR²⁴, CO₂R²⁴, NR²⁵R²⁶, NR²⁵COR²⁴, CONR²⁵R²⁶, SR²⁴,        SO₂R²⁴, CSR²⁴ or OSO₃R²⁴ group; advantageously from the group        consisting of a hydrogen atom, an halogen atom, a OH,        (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,        (C₃-C₇)-cycloalkyl, OR²⁴, COR²⁴, OCOR²⁴, CO₂R²⁴, NR²⁵R²⁶,        NR²⁵COR²⁴ and CONR²⁵⁻²⁶ group; more advantageously from the        group consisting of a hydrogen atom, an halogen atom, a OH,        (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,        (C₃-C₇)-cycloalkyl, OR²⁴, COR²⁴, OCOR²⁴ and CO₂R²⁴ group; even        more advantageously from the group consisting of a hydrogen        atom, an halogen atom, a OH, (C₁-C₆)-alkyl and OR²⁴ group.        Examples within this second subclass include but are not limited        to:

Compounds according to the invention can thus be selected from thefollowing compounds:

Another object of this invention is a compound as defined above, for useas a drug, in particular as an inhibitor of the sodium-dependent glucoseco-transporter, such as SGLT1, SGLT2 and SGLT3.

Within the meaning of this invention, “inhibitor of the sodium-dependentglucose co-transporter” is understood to mean a compound capable ofinhibiting partially or totally the sodium-dependent glucoseco-transporter.

More particularly, the compounds of the invention may be used fortreating or preventing diabetes, and more particularly type-II diabetes,diabetes-related complications, such as arteritis of the lowerextremities, cardiac infarction, renal insufficiency, neuropathy orblindness, hyperglycemia, hyperinsulinemia, obesity,hypertriglyceridemia, X syndrome and arteriosclerosis. The compounds ofthe invention are used in particular for treating or preventingdiabetes.

The compounds of the invention may likewise be used as an anti-cancer,anti-infective, anti-viral, anti-thrombotic or anti-inflammatory drug.

The invention likewise relates to a compound of the invention for itsuse in the treatment or prevention of diabetes, and more particularlytype-II diabetes, diabetes-related complications, such as arteritis ofthe lower extremities, cardiac infarction, renal insufficiency,neuropathy or blindness, hyperglycemia, hyperinsulinemia, obesity,hypertriglyceridemia, X syndrome and arteriosclerosis, as well as forits use as an anti-cancer, anti-infective, anti-viral, anti-thromboticor anti-inflammatory drug, and in particular in the treatment orprevention of diabetes.

The invention likewise relates to the use of a compound of the inventionfor the manufacture of a drug intended for the treatment or preventionof diabetes, and more particularly type-II diabetes, diabetes-relatedcomplications, such as arteritis of the lower extremities, cardiacinfarction, renal insufficiency, neuropathy or blindness, hyperglycemia,hyperinsulinemia, obesity, hypertriglyceridemia, X syndrome andarteriosclerosis, as well as for the manufacture of an anti-cancer,anti-infective, anti-viral, anti-thrombotic or anti-inflammatory drug,and in particular for the treatment or prevention of diabetes.

The invention likewise relates to a method for the treatment orprevention of diabetes, and more particularly type-II diabetes,diabetes-related complications, such as arteritis of the lowerextremities, cardiac infarction, renal insufficiency, neuropathy orblindness, hyperglycemia, hyperinsulinemia, obesity,hypertriglyceridemia, X syndrome and arteriosclerosis, as well as for ananti-cancer, anti-infective, anti-viral, anti-thrombotic oranti-inflammatory treatment, and in particular in for the treatment orprevention of diabetes, including the administration of an effectiveamount of at least one compound of the invention to a patient in needthereof.

Silylated compounds of the present invention, as well as compounds withR=CH₂OBn, R₁=OBn, R₂=OBn and/or R₃=OBn, will not be preferred for theiruse as medicament.

The compounds useful as a drug, and notably in the treatment orprevention of diabetes, are more particularly the compounds of formula(Ia) or (Ib), and in particular (Ia); notably the compounds of formula(I-2) to (I-5), such as (I-2a) to (I-5a) and (I-2b) to (I-5b), and inparticular (I-2a) to (I-5a).

Another object of this invention is the cosmetic use of a compound ofthe invention as defined above, for lightening, bleaching, depigmentingthe skin, removing blemishes from the skin, particularly age spots andfreckles, or preventing pigmentation of the skin, or as antioxidant, viatopical application in particular.

The present invention relates thus to a method for lightening,bleaching, depigmenting the skin, removing blemishes from the skin,particularly age spots and freckles, or preventing pigmentation of theskin, comprising the topical application of at least one compound of theinvention.

Silylated compounds of the present invention, as well as compounds withR=CH₂OBn, R₁=OBn, R₂=OBn and/or R₃=OBn, will not be preferred for theircosmetic use.

The compounds useful in the cosmetic field, in particular asdepigmenting or lightening agents, are more particularly the compoundsof formula (Ia), (Ib) or (Ic), and in particular (Ic); notably thecompounds of formula (I-1), such as (I-1a), (I-1b) and (I-1c), and moreparticularly (I-1c).

In particular, compounds with depigmenting activity are tyrosinaseinhibitors. They are in particular compounds of the following formula:

and preferably a compound of the following formula:

Another object of this invention is a pharmaceutical or cosmeticcomposition including at least one compound of the invention as definedabove and at least one pharmaceutically or cosmetically acceptablevehicle.

The compounds according to the invention can be administered orally,sublingually, parenterally, subcutaneously, intramuscularly,intravenously, transdermally, locally or rectally.

In the pharmaceutical compounds of this invention, for oral, sublingual,parenteral, subcutaneous, intramuscular, intravenous, transdermal, localor rectal administration, the active ingredient can be administered inunit forms of administration, mixed together with conventionalpharmaceutical carriers, for animals or human beings. Suitable unitforms of administration include oral forms such as tablets, gelcapsules, powders, granules and oral solutions or suspensions,sublingual or buccal forms of administration, parenteral, subcutaneous,intramuscular, intravenous, intranasal or intraocular forms ofadministration and rectal forms of administration.

When a solid composition is prepared in the form of tablets, theprincipal active ingredient is mixed with a pharmaceutical vehicle suchas gelatine, starch, lactose, magnesium stearate, talc, gum arabic orthe like. The tablets can be coated with sucrose or other suitablematerials or else treated in such a way that they have an extended ordelayed activity and continuously release a predetermined amount ofactive principle.

A gel capsule preparation is obtained by mixing the active ingredientwith a diluent and by pouring the mixture obtained into soft or hardcapsules.

A preparation in the form of a syrup or elixir can contain the activeingredient in conjunction with a sweetening agent, antiseptic, as wellas a flavour-producing agent and appropriate colouring agent.

Powders or granules dispersible in water can contain the activeingredient mixed together with dispersing agents, wetting agents, orsuspending agents, as well as with taste correctors or sweeteningagents.

For rectal administration, suppositories are used, which are preparedwith binding agents melting at rectal temperature, e.g., cocoa butter orpolyethylene glycols.

For parenteral, intranasal or intraocular administration, aqueoussuspensions are used, isotonic saline solutions or sterile andinjectable solutions, which contain pharmacologically compatibledispersing agents and/or wetting agents.

The active principle can also be formulated as microcapsules, possiblywith one or more additive carriers.

The compounds of the invention can be used at doses of between 0.01 mgand 1000 mg per day, given in a single dose once a day or administeredin several doses throughout the day, e.g., twice daily in equal doses.The daily dose administered is advantageously between 0.1 mg and 100 mg,even more advantageously between 2.5 mg and 50 mg. It may be necessaryto use doses exceeding these ranges, of which those skilled in the artwill themselves be aware.

In one particular embodiment of the invention, the pharmaceutical orcosmetic composition can also be formulated for topical administration.It may be introduced in forms commonly known for this type ofadministration, i.e., in particular, lotions, foams, gels, dispersions,sprays, shampoos, serums, masks, body milks or creams, for example, withexcipients enabling, in particular, penetration of the skin so as toimprove the properties and accessibility of the active principle.Besides the composition according to the invention, these compositionsgenerally further contain a physiologically acceptable medium, whichgenerally contains water or a solvent, e.g., alcohols, ethers orglycols. They can also contain surface-active agents, preservatives,stabilizers, emulsifiers, thickeners, other active principles producinga complementary or possibly synergic effect, trace elements, essentialoils, perfumes, colouring agents, collagen, chemical or mineral filters,hydrating agents or thermal waters.

In one particular embodiment, the pharmaceutical composition of theinvention may include at least one other active principle, in additionto the compound of the invention.

Examples of active principles that can be cited are antidiabetic agents,such as sulfonylurea-type compounds which are hypoglycemic sulfamideswhich increase insulin secretion like, e.g., chlorpropamide,tolbutamide, tolazamide, glipizide, gliclazide, glibenclamide,gliquidone and glimepiride, biguanides which reduce the hepaticglyconeogenesis and the insulin resistance like metformine,thiazolidinediones (also called glitazones) which increase thesensibility to insulin like rosiglitazone, pioglitazone and ciglitazone,alpha-glucosidases inhibitors which slow down the intestinal absorptionof carbohydrates like acarbose, miglitol and voglibose, meglitinides(also called glitinides) which increase insulin pancreatic secretionlike repaglinide and nateglinide, incretin mimics like exenatide ordipeptidylpeptidase-4 (DPP4) inhibitors like sitagliptin, vildagliptinand insulin, or antilipidic agents, such as statins which reducecholesterol by inhibiting the enzyme HMG-CoA reductase like atorvastatinand cerivastatin, fibrates like bezafibrate, gemfibrozil andfenofibrate, or ezetimibe.

The present invention concerns also processes for preparing a compoundaccording to the invention.

The present invention concerns thus a process for preparing a compoundof formula (I) according to the invention for which R₄=H comprising thefluorination of a compound of the following formula (II):

wherein R, R₁, R₂, R₃, X₁, U, V, W, n, m and p are as defined above.

The fluorination will be carried out in the presence of a fluorinatingagent, such as DAST (diethylaminosulphurtrifluoride).

If necessary additional steps of protection, deprotection, substitution,etc. can be carried out, these steps being well known to the personskilled in the art.

The compound of formula (I) obtained can be recovered by separation fromthe reaction medium by methods well known to the person skilled in theart, such as by extraction, evaporation of the solvent or byprecipitation or crystallisation (followed by filtration).

The compound can be also purified if necessary by methods well known tothe person skilled in the art, such as by recrystallisation, bydistillation, by chromatography on a column of silica gel or by highperformance liquid chromatography (HPLC).

The compound of formula (II) can be prepared by oxidation of a compoundof the following formula (III):

wherein R, R₁, R₂, R₃, X₁, U, V, W, n, m and p are as defined above.

The oxidation will be carried out in the presence of an oxidantaccording to procedures well known to the person skilled in the art. Theoxidant can be for example Dess-Martin periodinane, PCC (Pyridiniumchlorochromate), etc.

When n=1, the process for preparing the compound of formula (III) cancomprise the following successive steps:

-   -   (a1) coupling between a compound of the following formula (IV):

-   -   -   wherein R, R₁, R₂ and R₃ are as defined above,        -   and a compound of the following formula (V):

-   -   -   wherein X₁, U, V, W, m and p are as defined above,        -   to give a compound of the following formula (VI):

-   -   -   wherein R, R₁, R₂, R₃, X₁, U, V, W, m and p are as defined            above, and

    -   (b1) hydroboration-oxidation reaction of the compound of        formula (VI) obtained in previous step (a1) to give a compound        of formula (III) with n=1.

Step (a1) can be carried out in the conditions of the Mitsunobu reactionwell known to the person skilled in the art, notably using DEAD (diethylazo dicarboxylate), DIAD (diisopropyl azo dicarboxylate) or ADDP(azodicarboxylic acid dipiperidine) as coupling agent and PPh₃ orP(nBu)₃ as phosphine.

Step (b1) can be carried out in conditions well known to the personskilled in the art, notably by reaction with a borane such as BH₃, andin particular BH₃.THF or BH₃.Me₂S, in a solvent such as THF, followed bythe addition of hydrogen peroxide in the presence of a base such assodium hydroxide.

When n=0, the process for preparing the compound of formula (III) cancomprise the following successive steps:

-   -   (a2) coupling between a compound of the following formula (VII):

-   -   -   wherein R, R₁, R₂ and R₃ are as defined above,        -   and a compound of the following formula (VIII):

-   -   -   wherein X₁, U, V, W, m and p are as defined above and A₁            represents —Li or —Mg-Hal, Hal being a halogen atom,        -   to give a compound of the following formula (IX):

-   -   -   wherein R, R₁, R₂, R₃, X₁, U, V, W, m and p are as defined            above,

    -   (b2) reduction of the compound of formula (IX) obtained in        previous step (a2) to give a compound of the following formula        (X):

-   -   -   wherein R, R₁, R₂, R₃, X₁, U, V, W, m and p are as defined            above, and

    -   (c2) hydroboration-oxidation reaction of the compound of        formula (X) obtained in previous step (b2) to give a compound of        formula (III) with n=0.

Step (a2) can be carried out through the reaction of compound of formula(VIII) obtained from the halogenated derivative by reaction withmagnesium to form the Grignard reagent or by halogen exchange using alithium base such as n-butyllithium to form the corresponding lithiatedcompound, with compound of formula (VII), in a solvent such as THF.

Such compound of formula (VII) is obtained in conditions well known tothe person skilled in the art, and notably according to a processdescribed in EP0240175 or Carbohydrate Research 2010, 345, 1056-1060.

The compound of formula (VIII) can be obtained from the halogenatedderivative by reaction with magnesium to form the Grignard reagent or byhalogen exchange using a lithium base such as n-butyllithium to form thecorresponding lithiated compound.

Step (b2) can be carried out in the presence of a reducing agent such asEt₃SiH and a Lewis acid such as BH₃.Et₂O.

Step (c2) corresponds to previous step (b1).

The process to prepare compounds according to the invention with R₄=Hwill be better detailed below and in the following experimental part.

-   -   (a) In a first step cyclohexenone T1 undergoes a reduction        involving standard conditions such as NaBH₄, NaBH₄/CeCl₃, LiAlH₄        or L-selectride.    -   (b) A Mitsunobu-coupling reaction between compound T2 and        alcohol T3 then occurs under standard conditions using DEAD,        DIAD or ADDP as coupling agent and PPh₃ or P(nBu)₃ as phosphine.    -   (c) Hydroboration of compound T4 using BH₃.THF or BH₃.Me₂S leads        to compound T5.    -   (d) The alcohol function of compound T5 is oxidized into a        ketone according to typical procedures involving PCC,        Dess-Martin periodinane yielding compound T6.    -   (e) Compound T6 can be fluorinated using fluorinating agent such        as DAST to afford the difluorocarbasugar T7. In a last step,        protective groups can be removed according to typical procedures        described in Protective groups (Protective groups in organic        synthesis, T. W. Greene).        -   More particularly:

-   -   (a) In a first step cyclohexenone T8 undergoes a regioselective        reduction involving lithium tri-sec-butylborohydride as        described in Can. J. Chem 2004, 82, 1361-1364.    -   (b) A Mitsunobu-coupling reaction between compound T9 and        alcohol T3 then occurs under standard conditions using DEAD,        DIAD or ADDP as coupling agent and PPh₃ or P(nBu)₃ as phosphine.    -   (c) Hydroboration of compound T10 using BH₃.THF or BH₃.Me₂S        leads to compound T11.    -   (d) The alcohol function of compound T11 is oxidized into a        ketone according to typical procedures involving PCC,        Dess-Martin periodinane yielding compound T12.    -   (e) Compound T12 can be fluorinated using fluorinating agent        such as DAST to afford the difluorocarbasugar T13. In a last        step, protective groups can be removed according to typical        procedures described Protective groups in organic        synthesis, T. W. Greene.

Cyclohexenone T8 was prepared according to EP0240175 or Cumpstey, I.Carbohydrate Research 2010, 345, 1056-1060, applying the synthesis tothe glucose series from the commercially available2,3,4,6-O-benzyl-D-glucopyranose.

Compound T3 can be either commercially available (first subclass) orsynthesized according to:

(second subclass)

Or

(R₅ and R₆ representing a (C₁-C₆)alkyl group) (third subclass)

-   -   (a) In a first step, a Grignard reagent or a lithiated compound        T14, prepared from the corresponding halogenated compound        according to a typical procedure, is added onto cyclohexenone        T1.    -   (b) In the next step of the synthesis, compound T15 is treated        with a reducing agent such as Et₃SiH in the presence of a Lewis        acid such as BF₃.Et₂O, yielding compound T16.    -   (c) Hydroboration of compound T16 using BH₃.THF or BH₃.Me₂S        leads to compound T17.    -   (d) The alcohol function of compound T17 is oxidized into a        ketone according to typical procedures involving PCC,        Dess-Martin periodinane yielding compound T18.    -   (e) Compound T18 can be fluorinated using fluorinating agent        such as DAST to afford the difluorocarbasugar T19. In a last        step, protective groups can be removed according to typical        procedures described in Protective groups in organic        synthesis, T. W. Greene.        -   And more particularly:

-   -   (a) In a first step, a Grignard reagent or a lithiated compound        T14, prepared from the corresponding halogenated compound        according to a typical procedure, is added onto cyclohexenone        T8.    -   (b) In the next step of the synthesis, compound T20 is treated        with a reducing agent such as Et₃SiH in the presence of a Lewis        acid such as BF₃.Et₂O, yielding compound T21.    -   (c) Hydroboration of compound T21 using BH₃.THF or BH₃.Me₂S        leads to compound T22.    -   (d) The alcohol function of compound T22 is oxidized into a        ketone according to typical procedures involving PCC,        Dess-Martin periodinane yielding compound T23.    -   (e) Compound T23 can be fluorinated using fluorinating agent        such as DAST to afford the difluorocarbasugar T24. In a last        step, protective groups can be removed according to typical        procedures described in Protective groups in organic        synthesis, T. W. Greene.

Halogenated compound giving access to compound T14 can be synthesizedaccording to the following scheme:

The present invention concerns also a process for preparing a compoundof the formula (I) according to the invention for which n=0 and R₄≠Hcomprising the coupling of a compound of formula (VIII) as defined aboveand a compound of the following formula (XI)

wherein R, R₁, R₂, and R₃ are as defined above,to give a compound of formula (I) for which n=0 and R₄=OH,followed optionally by the substitution of the OH function to give acompound of formula (I) for which n=0 and R₄=halogen,OSiR^(j)R^(k)R^(l), OR²¹, OCOR²¹, OCO₂R²¹, or OCONR²²R²³.

These steps of coupling and substitution can be carried out inconditions well known to the person skilled in the art.

If necessary additional steps of protection, deprotection, substitution,etc. can be carried out, these steps being well known to the personskilled in the art.

The compound of formula (I) obtained can be recovered by separation fromthe reaction medium by methods well known to the person skilled in theart, such as by extraction, evaporation of the solvent or byprecipitation or crystallisation (followed by filtration).

The compound can be also purified if necessary by methods well known tothe person skilled in the art, such as by recrystallisation, bydistillation, by chromatography on a column of silica gel or by highperformance liquid chromatography (HPLC).

The process for preparing the compound of formula (XI) can comprise thefollowing successive steps:

-   -   (a3) hydroboration-oxidation reaction of the compound of formula        (XII)

-   -   -   wherein R, R₁, R₂, and R₃ are as defined above and            R₇=SiR^(a1)R^(b1)R^(c1) or CH₂OCH₃ (methoxymethyl—MOM), with            R^(a1), R^(b1) and R^(c1) each representing independently a            (C₁-C₆)-alkyl, aryl or aryl-(C₁-C₆)-alkyl group,        -   to give a compound of the following formula (XIII)

-   -   -   wherein R, R₁, R₂, and R₃ are as defined above and            R₇=SiR^(a1)R^(b1)R^(c1) or CH₂OCH₃ (methoxymethyl—MOM),

    -   (b3) oxidation of the compound of formula (XIII) obtained in        previous step (a3) to give a compound of the following formula        (XIV)

-   -   -   wherein R, R₁, R₂, and R₃ are as defined above and            R₇=SiR^(a1)R^(b1)R^(c1) or CH₂OCH₃ (methoxymethyl—MOM),

    -   (c3) when R₇=SiR^(a1)R^(b1)R^(c1), deprotection of the compound        of formula (XIV) obtained in previous step (b3) to give a        compound of formula (XIV) with R₇=H,

    -   (d3) when R₇=H, protection of the compound of formula (XIV) with        R₇=H obtained in previous step (c3) to give a compound of        formula (XIV) with R₇=COR₈ with R₈ representing a (C₁-C₆)-alkyl,        aryl or aryl-(C₁-C₆)-alkyl group,

    -   (e3) fluorination of the compound of formula (XIV) with R₇=COR₈        or CH₂OCH₃ obtained in previous step (d3) or (b3) to give a        compound of the following formula (XV)

-   -   -   wherein R, R₁, R₂, and R₃ are as defined above and R₇=COR₈            or CH₂OCH₃,

    -   (f3) deprotection of the compound of formula (XV) with R₇=COR₈        or CH₂OCH₃ obtained in previous step (e3) to give a compound of        formula (XV) with R₇=H, and

    -   (g3) oxidation of the compound of formula (XV) with R₇=H        obtained in previous step (f3) to give a compound of formula        (XI).

Step (a3) corresponds to previous step (b1). Compound of formula (XII)can be prepared from compound of formula (IV) by a protection step, wellknown to the person skilled in the art.

Steps (b3) and (g3) can be carried out in the presence of an oxidantsuch as Dess-Martin periodinane, PCC (Pyridinium chlorochromate), etc.

Steps (c3) and (d3) are optional and required only whenR7=SiR^(a1)R^(b1)R^(c1) in the starting material of formula (XII).

Step (c3), (d3) and (f3) can be carried out in conditions well known tothe person skilled in the art.

Step (e3) can be carried out in the presence of a fluorinating agent,such as DAST (diethylaminosulphurtrifluoride).

The present invention concerns also a process for preparing a compoundof formula (I) according to the invention for which R₄=H comprising thefollowing steps:

-   -   (a4) bromination of a compound of formula (I) with R₄=OH to give        a compound of formula (I) with R₄=Br, and    -   (b4) reduction of the compound of formula (I) with R₄=Br        obtained in previous step (a4) to give a compound of formula (I)        with R₄=H.

Step (a4) can be carried out in the presence of a brominating agent suchas SOBr₂. The reaction is advantageously carried out also in thepresence of a base such as pyridine. The starting material can beprepared according to the process described above to prepare compoundsof formula (I) with R₄≠H.

Step (b4) can be carried out in the presence of a hydride such asBu₃SnH.

The process to prepare compounds according to the invention with n=0 andR₄=OH or H will be better detailed below and in the followingexperimental part.

-   -   (a) In a first step cyclohexenone T1 undergoes a reduction        involving standard conditions such as NaBH₄, NaBH₄/CeCl₃, LiAlH₄        or L-selectride.    -   (b) Alcohol T2 is then protected in the form of a silyl ether,        according to well known procedures described in Protective        groups in organic synthesis, T. W. Greene, to give compound T25.    -   (c) Hydroboration of compound T25 using BH₃.Me₂S or BH₃.THF        leads to compound T26.    -   (d) Compound T26 is then oxidized into the corresponding ketone        T27 according to typical procedures involving PCC, Dess-Martin        periodinane, etc.    -   (e) When T27 bears a R₇ which is a silylated protective group,        this silylated protective group of compound T27 is then removed        under acidic conditions using typical procedures described in        Protective groups in organic synthesis, T. W. Greene, to afford        alcohol T28.    -   (f) This alcohol T28 is protected into an ester according to        well known procedures described in Protective groups in organic        synthesis, T. W. Greene, to give compound T29.    -   (g) Compound T27 (when R₇=MOM) or T29 is fluorinated using a        fluorinated reagent such as DAST to afford the fluorinated        compound no.    -   (h) The ether or ester protective group (OR₇) of compound T30 is        removed under typical conditions described in Protective groups        in organic synthesis, T. W. Greene, to afford alcohol T31.    -   (i) This alcohol T31 is then oxidized using Dess-Martin        periodinane to afford compound T32.    -   (j) A Grignard reagent or lithiated compound T14, prepared from        the corresponding halogenated compound according to a typical        procedure, is added onto compound T32 to afford T33.    -   (k) Compound T33 is brominated according to typical procedures        including the use of SOBr₂ followed by the addition of pyridine        to afford compound T34.    -   (l) Compound T34 is then reduced in the presence of a hydride        such as Bu₃SnH.    -   (m) In a last step, protective groups can be removed according        to typical procedures described in Protective groups in organic        synthesis, T. W. Greene.

It should be noted that steps (k) and (l) are carried out only for thepreparation of a compound of formula (I) with R₄=H.

And more particularly:

-   -   (a) In a first step cyclohexenone T8 undergoes a selective        reduction involving NaBH₄/CeCl₃, in THF and MeOH.    -   (b) Alcohol T36 is then protected using imidazole and TBDMSCl to        give compound T37 with R₇=TBDMS; or dimethoxymethane and P₂O₅ to        give compound T37 with R₇=CH₂OCH₃.    -   (c) Hydroboration of compound. T37 using BH₃.Me₂S leads to        compound T38.    -   (d) Compound T38 is then oxidized into the corresponding ketone        T39 according to typical procedures involving PCC, Dess-Martin        periodinane, etc.    -   (e) When R₇=TBDMS, this silylated protective group of compound        T39 is then removed under acidic conditions such as HCl 12N in        methanol and dichloromethane to afford alcohol T40.    -   (f) This alcohol T40 is protected into an acetate using Ac₂O,        pyridine and a catalytic amount of DMAP (Dimethylaminopyridine)        to give compound T41.    -   (g) Compound T41 or compound T39 with R₇=CH₂OCH₃ is fluorinated        using DAST in dichloromethane to afford the fluorinated compound        T42.    -   (h) When R₇=Ac, the acetate protecting group of compound T42 is        removed using sodium methanolate in methanol to afford alcohol        T43.        -   When R₇=CH₂OCH₃, the MOM protective group of T42 is removed            using TFA in dichloromethane to afford alcohol T43.    -   (i) This alcohol T43 is then oxidized using Dess-Martin        periodinane to afford compound T44    -   (j) A Grignard reagent or a lithiated compound T14, prepared        from the corresponding halogenated compound according to a        typical procedure, is added onto compound T44 to give compound        T45.    -   (k) Compound T45 is brominated with SOBr₂ in dichloromethane        followed by the addition of pyridine to afford compound T46.    -   (l) Compound T46 is then reduced in the presence of Bu₃SnH in        toluene to give compound T47.    -   (m) In a last step, protective groups can be removed according        to typical procedures described in Protective groups in organic        synthesis, T. W. Greene.

It should be noted that steps (k) and (l) are carried out only for thepreparation of a compound of formula (I) with R₄=H.

The present invention concerns also a process for preparing a compoundof formula (I) according to the invention for which R4=H and n=1comprising a coupling reaction between a compound of the followingformula (XVI):

wherein R, R₁, R₂, and R₃ are as defined above and R₉ represents aleaving group, with a compound of formula (V) as defined above.

The term “leaving group” as used in the present invention refers to achemical group which can be easily replaced with a nucleophile during anucleophile substitution reaction, the nucleophile being in the presentcase an alcohol, i.e. a molecule carrying a group OH. Such a leavinggroup can be in particular a halogen atom or a sulfonate. The sulfonateis in particular a group —OSO2-R10 with R10 representing a (C1-C6alkyl),aryl, aryl-(C1-C6)-alkyl or (C1-C6)-alkyl-aryl group. The sulfonate canbe in a mesylate (CH3-S(O2)O—), a triflate (CF3-S(O)2O—) or a tosylate(p-Me-C6H4-S(O)2O—).

This reaction can be carried out in conditions well known to the personskilled in the art, notably in the presence of a base such as NaH,K₂CO₃, or MeONa.

If necessary, additional steps of protection, deprotection,substitution, etc. can be carried out, these steps being well known tothe person skilled in the art.

The compound of formula (I) obtained can be recovered by separation fromthe reaction medium by methods well known to the person skilled in theart, such as by extraction, evaporation of the solvent or byprecipitation or crystallisation (followed by filtration).

The compound can be also purified if necessary by methods well known tothe person skilled in the art, such as by recrystallisation, bydistillation, by chromatography on a column of silica gel or by highperformance liquid chromatography (HPLC).

The compound of formula (XVI) can be prepared from a compound of formula(XV) wherein R₇=H according to procedures well known to the personskilled in the art. For example, when the leaving group is a halogenatom, the reaction can be carried out in the presence of a halogenatingagent. When the leaving group is a sulfonate, the reaction can becarried out in the presence of the corresponding sulfonic acid and abase such as pyridine.

The process to prepare compounds according to the invention with n=1 andR₄=H will be better detailed below and in the following experimentalpart.

-   -   (a) In a first step, the alcohol group of T31 is converted into        a leaving group such as a halogen or a mesyl, tosyl or        trifluoromethanesulfonyl group according to procedures well        known of the person skilled in the art.    -   (b) T48 is then substituted by the alcoholate generated from T3        by the use of a base such as NaH, K₂CO₃, or MeONa, to afford T7.    -   (c) In a last step, protective groups can be removed according        to typical procedures described in Protective groups in organic        synthesis, T. W. Greene.        And more particularly:

-   -   (a) In a first step, the alcohol group of T43 is converted into        its corresponding trifluoromethanesulfonyl group in the presence        of trifluoromethanesulfonic anhydride and pyridine to afford        compound T49.    -   (b) T49 is then substituted by the alcoholate generated from T3        by the use of NaH to give T50. The reaction is performed in        dimethylformamide.    -   (c) In a last step, protective groups can be removed according        to typical procedures described in Protective groups in organic        synthesis, T. W. Greene.

The invention will be better understood upon reading the followingexamples and figures, these examples serving solely to illustrate theinvention.

FIGURES

FIG. 1 represents urinary glucose excretion for compound 16 and forcompound 50 between 0 and 8 hours following oral administration (3 mg/kgpo).

FIG. 2 represents urinary glucose excretion for compound 16 and forcompound 50 between 16 and 28 hours following oral administration (3mg/kg po).

FIG. 3 represents oral glucose tolerance test for compound 16 at 1, 3and 10 mg/kg po.

FIG. 4 represents oral glucose tolerance test for compound 16 18 hourspost oral administration of compound 16 (3 mg/kg po).

FIG. 5 represents urinary glucose excretion for compound 16 and forcompound 50 between 16 and 28 hours following oral administration (3mg/kg po).

FIG. 6 represents urinary glucose excretion for compound 16 and forcompound 9 of WO2009/1076550 between 16 and 28 hours following oraladministration (3 mg/kg po).

FIG. 7 represents the HPLC spectrum of compound M.

FIG. 8 represents the HPLC spectrum of compound 26.

FIG. 9 represents the HPLC spectrum of compound 26 after 4 h ofincubation at 37° C. in the presence of β-glucosidase.

FIG. 10 represents the HPLC spectrum of Sergliflozin-A.

FIG. 11 represents the HPLC spectrum of Sergliflozin-A after 4 h ofincubation at 37° C. in the presence β-glucosidase.

EXAMPLES 1. Preparation of the Compounds of the Invention

The abbreviations encountered are defined as follows:

-   Ac acetyl-   ADDP azodicarboxylic acid dipiperidine-   Bn benzyl-   cat. Catalytic-   DAST diethylaminosulphurtrifluoride-   DCM dichloromethane-   de diastereomeric excess-   DMAP 4-Dimethylaminopyridine-   DMF dimethylformamide-   DMSO dimethylsulfoxide-   eq. equivalent-   ESI electrospray ionisation-   g gram-   Hz Hertz-   mg milligram-   MHz megahertz-   min. minute-   mL milliliter-   mmol millimole-   mM millimolar-   μmol micromole-   nmol nanomole-   NMR Nuclear Magnetic Resonance-   po per os-   PEG Polyethylene glycol-   QS Quantum Satis-   Rf rate of flow-   rt room temperature-   TFAA trifluoroacetic anhydride-   THF tetrahydrofurane-   TLC Thin layer Chromatography-   TMS trimethylsilyl-   TBDMS Tert-butyldimethylsilyl

The features of the devices used to conduct analyses of all of thecompounds described in this application are indicated herein below:

The ¹⁹F NMR spectra were recorded on BRUKER DPX 300 spectrometer. Theinternal reference used is fluorotrichloromethane CFCl₃. Chemical shifts(δ) are expressed in parts per million (ppm), and coupling constants (J)in Hertz (Hz).

The following abbreviations were used:

s for singlet, bs for broad singlet, d for doublet, t for triplet, qdtfor quartet, m for multiplet or massive, dd for doublet of doublet, etc.

The mass spectra were obtained on a spectrophotometer Waters LCT PremierXE coupled to a LC Waters Acquity.

GC-MS spectra were performed on a Micromass Autospec 8 kV, equipped witha GC HP 6890, Capillar column WCOT, HP 5 MS, 30 m, DI: 0.25 mm, at 50°C. (0.5 mn), from 50 to 280° C. at 10° C./mn, and 280° C. for 5 mn, withIE: 70 eV.

Automated column chromatography was performed on Biotage SP4 instrumentsusing Biotage® SNAP cartridges. Follow-up is ensured via thin-layerchromatography (TLC) with Kieselgel 60E-254-0.25-mm plates. The ratio ofthe migration distance of a compound on a given support to the migrationdistance of an eluent is called the retardation factor (Rf).

Exemplary compound preparations according to the invention will bedescribed hereinbelow, for non-limiting, illustrative purposes.

Synthesis of Compound 1

C₃₄H₃₄O₆ M=538.63 g·mol⁻¹

Mass: (ESI⁺): 561.2 (M+Na)

Acetic anhydride (420 mL) was added to a round bottom flask under inertatmosphere containing 2,3,4,6-tetra-O-benzyl-D-glucopyranose (100 g, 185mmol) in DMS (640 mL). The mixture was stirred overnight at roomtemperature before being cooled to 0° C. A large volume of water wasadded and stirring was stopped so that the reaction mixture was allowedto settle for 3 h (the crude lactone lies at the bottom of the flask).The supernatant was removed and the crude mixture was diluted with Et₂Oand washed 3 times with water, neutralised with saturated aqueoussolution of NaHCO₃ and washed again twice with water. The organic layerwas then dried over magnesium sulphate, filtered and concentrated. Thecrude mixture was purified by silica gel chromatography(cyclohexane/ethyl acetate 8:2; Rf=0.61) to afford the desired lactone 1as a colourless oil with 80% yield.

Synthesis of Compound 2

C₃₇H₄₃O₉P M=662.71 g·mol⁻¹

Mass: (ESI⁺): 685.33 [M+Na]⁺; 1346.80 [2M+Na]⁺

Under inert atmosphere, n-butyllithium (1.6M solution in hexanes, 168mL, 0.27 mol, 2.9 eq) was added dropwise to a solution of dimethylmethyl-phosphonate (42 mL, 0.39 mol, 4.2 eq) in THF (390 mL) cooled to−78° C. The mixture was stirred for 30 minutes at this temperaturebefore a solution of lactone 1 (50 g, 93 mmol, 1 eq) in tetrahydrofuran(230 mL) was added dropwise at the same temperature. The mixture wasstirred for 30 minutes before being allowed to warm to 0° C. withstirring.

The reaction mixture was poured into an ice-cooled mixture of 10%saturated ammonium chloride aqueous solution (100 mL) and ethyl acetate(300 mL). The organic layer was separated, washed with water, dried oversodium sulphate, filtered and then concentrated under reduced pressureto afford quantitatively3,4,5,7-tetra-O-benzyl-1-deoxy-1-(dimethoxyphosphoryl)-D-gluco-2-heptulopyranose2 (63 g) as a slightly yellowish oil which gives white crystalsovertime.

Synthesis of Compounds 3a/b

C₃₇H₄₅O₉P M=664.72 g·mol⁻¹

Mass: (ESI⁺): 665.13 (M+H); 687.27 (M+Na); 696.73 (M+MeOH)

To a solution of 2 (69.5 g, 105 mmol, 1 eq) in tetrahydrofuran (600 mL)was added by portion sodium borohydride (7.44 g, 210 mmol, 2 eq). Themixture was stirred overnight at room temperature prior to beconcentrated under reduced pressure. The residue was partitioned betweenethyl acetate and water and the organic layer was washed with water,dried over sodium sulphate, filtered and concentrated under reducedpressure. The crude compound 3 (mixture of diastereomers a and b, 70.5g, 100%) was engaged in the next step without further purification.

Synthesis of Compound 4

C₃₇H₄₁O₉P M=660.69 g·mol⁻¹

Mass: (ESI⁺): 661.00 (M+H); 683.20 (M+Na); 1343.0 (2M+Na)⁺

A solution of trifluoroacetic anhydride (27.1 mL, 0.19 mol, 4 eq) indichloromethane (130 mL), cooled to 0° C. was added dropwise under inertatmosphere to a solution of dimethylsulfoxide (20.8 mL, 0.29 mol, 6 eq)in dichloromethane (260 mL) prepared at ambient temperature before beingcooled to −75° C. The mixture was stirred for 45 minutes at −75° C.,before a solution of 3 (32.43 g, 48.8 mmol, 1 eq) in dichloromethane(260 mL) cooled to −75° C. was added. The mixture was stirred for 1.5 hat the same temperature. Triethylamine (54.2 mL, 0.39 mmol, 8 eq) wasadded dropwise to the reaction mixture which was then allowed to warm to0° C. with stirring. A 2N hydrochloric acid aqueous solution was addedto the reaction mixture. The organic layer was separated, washed with asaturated sodium hydrogenocarbonate solution, dried over sodiumsulphate, filtered and concentrated under reduced pressure. The crudecompound 4 (36.3 g, 100%), obtained in the form of a yellowish oil wasengaged in the next step without further purification.

Synthesis of Compounds 5a/b

C₃₅H₄₀O₆ M=556.69 g·mol⁻¹

Mass: (ESI⁺): 557.20 (M+H); 1135.07 (2M+Na)

2,3,4,6-tetra-O-benzyl-D-glucopyranose (50 g, 92.7 mmol, 1 eq) wasdissolved in THF (645 mL) and cooled to 0°. Methylmagnesium bromide (185mL of a 1.4M solution in THF/toluene, 259.4 mmol, 2.8 eq) was addeddropwise under inert atmosphere and the reaction mixture was stirred for10 min at 0° C. and 3 h 30 at 50° C. TLC (cyclohexane-ethyl acetate,7:3) showed complete conversion of starting material into two products(Rfa=0.17 and Rfb=0.25). The reaction mixture was poured into asaturated aqueous solution of ammonium chloride and extracted with ethylacetate. The combined organic extracts were dried over sodium sulphate,filtered and concentrated to afford quantitatively the desired crudediol 5 (as a mixture of diastereomers a and b) in the form of yellowoil. This compound was engaged in the following step without furtherpurification.

Synthesis of Compound 6

C₃₅H₃₆O₆ M=552.66 g·mol⁻¹

Mass: (ESI⁺): 575.40 (M+Na); 575.40 (M+K); 1127.07 (2M+Na); 1142.93(2M+K)⁺.

A solution of dimethylsulfoxide (14 mL, 0.20 mol, 9 eq) indichloromethane (50 mL) was added dropwise to a solution of oxalylchloride (12.5 mL, 0.13 mol, 6 eq) in dichloromethane (50 mL) cooled to−78° C., under inert atmosphere. The mixture was stirred at −78° C. for30 min before a solution of diol 5 (12.2 g, 21.9 mmol, 1 eq) indichloromethane (50 mL) was added dropwise. After 45 min, a precipitateappeared and the reaction mixture was warmed to −40° C. and stirred foran additional 30 min. The mixture was then re-cooled to −78° C. andtriethylamine (55 mL, 0.39 mol, 18 eq) was added dropwise. After 15 min,the cooling bath was removed and the reaction mixture was allowed toreach room temperature. A large amount of precipitate had formed. Aftera further 2 h, toluene (400 mL) was added and the precipitate wasremoved by filtration. The residue was washed with toluene and thefiltrate was concentrated and purified by silica gel chromatography(cyclohexane/ethyl acetate 97:3 to 70:30) to afford diketone 6 (9.92 g,76% yield) as an orange oil.

Synthesis of Compound 7

C₃₅H₃₆O₆ M=552.66 g·mol⁻¹

Mass: (ESI⁺): 570.27 (M+H₂O); 575.33 (M+Na)

L-proline (7.35 g, 63.8 mmol, 1 eq) was added to a solution of diketone6 (35.2 g, 63.7 mmol, 1 eq) in DMSO (561 mL). The mixture was stirred at50° C. in air for 8 h before being poured into a mixture of water andbrine (2:1), extracted with ethyl acetate, dried over sodium sulphate,filtered and concentrated. The crude mixture was purified on silica gelchromatography (cyclohexane/ethyl acetate 97:3 to 35:35) to affordcompound 7 (13.0 g, 37%) as an orange oil.

Synthesis of Compound 8

C₃₅H₃₄O₅ M=534.64 g·mol⁻¹

Mass: (ESI⁺): 535.00 (M+H); 552.00 (M+H₂O); 785.87; 1086.67 (2M+H₂O)

Procedure A:

To a solution of 4 (10.5 g, 15.89 mmol, 1 eq) in toluene (400 mL) wereadded 18-crown-6 (168 mg, 0.64 mmol, 0.04 eq) and potassium carbonate(6.69 g, 48.5 mmol, 3.05 eq.). The mixture was stirred overnight at roomtemperature, and then the remising insoluble material was filtered offand washed with toluene. The filtrate and the washings were combined,washed with 2N hydrochloric acid aqueous solution followed by saturatedsodium hydrogencarbonate aqueous solution, dried over sodium sulphate,filtered and concentrated under reduced pressure. The residue waspurified on silica gel chromatography (cyclohexane/ethyl acetate 98:2 to80:20) to afford cyclohexenone 8 (4.07 g; 48% yield) as yellowish oil.

Procedure B:

A solution of 7 (3.27 g, 5.92 mmol, 1 eq) in pyridine (14 mL) was cooledto 0° C. before POCl₃ (2.75 mL, 29.6 mmol, 5 eq) was added dropwise. Themixture was stirred at this temperature for 10 min before the coolingbath was removed. The reaction mixture was stirred overnight at roomtemperature before being re-cooled to 0° C. POCl₃ (2.75 mL, 29.6 mmol, 5eq) was added once again trying to complete the reaction. The mixturewas stirred for an additional 20 h at room temperature before beingdiluted with Et₂O (20 mL) and poured onto crushed ice. 1M HCl aqueoussolution (100 mL) was added, and the mixture was extracted with Et₂O(200 mL & 100 mL). The combined organic extracts were washed with brine(100 mL), dried over sodium sulphate, filtered and concentrated beforebeing purified on silica gel chromatography (cyclohexane/ethyl acetate98:2 to 80:20) to afford compound 8 (1.46 g, 46% yield) as an orangeoil.

Synthesis of Compound 9

C₁₅H₁₂BrClO₂ M=339.61 g·mol⁻¹

Mass: (GC-MS): 338-340

The synthesis of this product is described in J. Med. Chem. 2008, 51,1145-1149.

Synthesis of Compound 10

C₁₅H₁₄BrClO M=325.63 g·mol⁻¹

The synthesis of this product is described in J. Med. Chem. 2008, 5.1,1145-1149.

Synthesis of Compound 11

C₅₀H₄₉ClO₆ M=781.37 g·mol⁻¹

Mass: (ESI⁺): 798.20 (M+H₂O)

Under inert atmosphere, Mg powder (265 mg, 10.9 mmol, 2.44 was chargedinto a three necked flask, followed by addition of a portion of ⅓ of asolution of the 4-bromo-1-chloro-2-(4-ethylbenzyl)benzene (2.95 g, 9.1mmol; 2 eq) in dry THF (25 mL) and 1,2-dibromoethane (10 mol % of Mg; 85mg; 0.45 mmol). The mixture was heated to reflux. After the reaction wasinitiated (exothermic and consuming of Mg), the remaining solution of2-(4-ethylbenzyl)-4-bromo-1-chlorobenzene in dry THF was added dropwise.The mixture was then allowed to react for another one hour under gentlereflux until most of the Mg was consumed.

The above Grignard reagent was added dropwise into the solution ofcyclohexenone 8 (2.42 g, 4.53 mmol, 1 eq) in dry THF (25 mL) under inertatmosphere at room temperature (about 25° C.), then allowed to react for3 h. A saturated aqueous solution of ammonium chloride was added intothe mixture to quench the reaction. The mixture was extracted with Et₂O,washed with brine, dried over sodium sulphate, filtered andconcentrated. The residue was purified on silica gel chromatography(cyclohexane/ethyl acetate 100:0 to 80:20) to afford the target compound11 as a yellow oil (3.01 g, 86%).

Synthesis of Compound 12

C₅₀H₄₉ClO₅ M=765.37 g·mol⁻

Mass: (ESI⁺): 782.13 (M+H₂O)

Triethylsilane (0.210 mL, 1.30 mmol, 3 eq) and boron-trifluorideetherate (48% BF₃, 0.110 mL, 0.866 mmol, 2 eq) were successively addedinto a solution of alcohol 11 (338 mg, 0.433 mmol, 1 eq) indichloromethane (5 mL) under inert atmosphere at −20° C. After stirringfor 2.5 h, a saturated aqueous solution of sodium chloride was added toquench the reaction. The mixture was extracted with CH₂Cl₂ (10 mL×3) andthe organic layer was washed with brine, dried over Na₂SO₄, filtratedand concentrated. The residue was purified on silica gel chromatography(cyclohexane/ethyl acetate 9.8:0.2 to 8:2) to afford the target compound12 as a white powder (278 mg, 0.363 mmol, 84%).

Synthesis of Compound 13

C₅₀H₅₁ClO₆ M=783.39 g·mol⁻¹

Mass: (ESI⁺): 800 (M+H₂O); 1581 (2M+H₂O)

Under inert atmosphere, borane-dimethyl sulfide complex (2M in THF, 16.7mL, 33 mmol, 10.5 eq) was added to a solution of 12 (2.41 g; 3.15 mmol,1 eq) in dry THF (100 mL) cooled to 0° C. The reaction mixture was thenrefluxed for 1 h, cooled to 0° C. and treated carefully with sodiumhydroxide (3M in H₂O, 10.5 mL, 31.5 mmol, 10 eq), followed by hydrogenperoxide (30% in H₂O, 3.2 mL, 31.5 mmol, 10 eq) at room temperature(above 30° C.). The mixture was allowed to react overnight at roomtemperature (˜25° C.) before a saturated aqueous solution of ammoniumchloride was added to quench the reaction. The mixture was extractedwith ethyl acetate and the organic layer was washed with brine, driedover Na₂SO₄, filtered, and concentrated. The residue was purified bysilica gel chromatography (cyclohexane/ethyl acetate 97:3 to 73:27) toafford the desired compound 13 (1.05 g; 43%) as a yellowish oil.

Synthesis of Compound 14

C₅₀H₄₉ClO₆ M=781.37 g·mol⁻¹

Mass: (ESI⁺): 798 (M+H₂O); 1471; 1579 (2M+H₂O)

Dess-Martin periodinane (81 mg; 1.91 mmol; 1.5 eq) was added portionwise to a solution of alcohol 13 (1.0 g; 1.28 mmol, 1 eq) in anhydrousdichloromethane (20 mL) at 0° C. The reaction was then stirred overnightat room temperature before being quenched with 1N aqueous solution ofsodium hydroxide. The organic layer was separated and the aqueous layerwas extracted with dichloromethane. The combined organic layers weredried over sodium sulphate, filtered and concentrated. The residue waspurified on silica gel chromatography (cyclohexane/ethyl acetate 98:2 to82:18), to afford the target ketone 14 (783 mg, 79% yield) as acolorless oil.

Synthesis of Compound 15

C₅₀H₄₉ClF₂O₆ M=803.37 g·mol⁻¹

¹⁹F NMR (CDCl₃, 282.5 MHz): −100.3 (d, J=254 Hz, 1F, CFF); −113.3 (td,J1=254 Hz, J2=29 Hz, 1F, CFF).

Mass: (ESI⁺): 820.00 (M+H₂O)

A solution of ketone 14 (421 mg, 0.539 mmol, 1 eq) in DAST (2 mL, 16.3mmol, 30 eq.) was stirred under inert atmosphere at 70° C. for 12 h. Themixture was then cooled to room temperature and dichloromethane wasadded. The solution was poured on a mixture of water, ice and solidNaHCO₃. Agitation was maintained for 30 min while reaching roomtemperature. The aqueous layer was extracted with dichloromethane andthe organic phase was dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified on silica gel chromatography(cyclohexane/ethyl acetate 98:2 to 80:20) to afford the desired compound15 as a yellowish oil (182 mg, 42% yield).

Synthesis of Compound 16

C₂₂H₂₅ClF₂O₅ M=442.88 g·mol⁻¹

¹⁹F NMR (MeOD, 282.5 MHz): −96.7 (d, J=254 Hz, 1F, CFF); −112.2 (td,J1=254 Hz, J2=28 Hz, 1F, CFF).

Mass: (ESI⁺): 465.3 (M+Na)

o-Dichlorobenzene (0.320 mL, 2.82 mol, 10 eq) followed by Pd/C 10%(0.342 g, 0.32 mol, 1.1 eq) were added to a solution of 15 (228 mg, 0.28mmol, 1 eq) in a mixture of THF and MeOH (2:1, v/v, 160 mL). Thereaction was placed under hydrogen atmosphere and stirred at roomtemperature for 2 h. The reaction mixture was filtered and concentratedbefore being purified on silica gel chromatography(dichloromethane/methanol 100:1 to 90:10) to afford compound 16 (105 mg,83% yield).

Synthesis of Compound 17

C₃₅H₃₆O₅ M=536.66 g·mol⁻¹

Mass: (ESI⁺): 554.13 (M+H₂O); 1095 (2M+Na)

A 1M solution of L-selectride in THF (0.84 mL, 0.84 mmol, 1.5 eq), wasadded dropwise to a stirred and cooled (0° C.) solution of cyclohexenone8 (0.300 g, 0.56 mmol, 1 eq) in THF (14 mL) under inert atmosphere. Themixture was stirred for 18 h allowing it to warm up to room temperaturegradually. A saturated aqueous solution of ammonium chloride was thenadded and the resultant mixture was stirred for an additional 15 min.Water was added and the aqueous solution was then extracted with ethylacetate and the combined organic layers were washed with brine, driedover sodium sulphate, filtered and concentrated to afford quantitativelythe desired compound 17 (350 mg) as a yellow oil.

Synthesis of Compound 18

C₁₄H₁₂O₃ M=228.24 g·mol⁻¹

Mass: (GC-MS): 228 (M)

Procedure A.

2-Hydroxybenzoic acid (13.8 g, 0.1 mol, 1 eq) and anisole (10.9 mL, 0.1mol, 1 eq) were added to a mixture of graphite (9.6 g, 0.8 mol, 8 eq)and methanesulfonic acid (25 mL, 0.4 mol, 4 eq) heated to 80° C. Thereaction mixture was stirred at this temperature for 12 h before beingcooled to room temperature. The mixture was then extracted twice withchloroform and the combined organic layers were washed with a saturatedaqueous solution of NaHCO₃, dried over sodium sulphate, filtered andconcentrated. The residue was purified on silica gel chromatography(cyclohexane/ethyl acetate 70:30) to afford compound 18 (4 g 17% yield)as an orange oil.

Procedure B.

BBr₃.DMSO (10.8 g, 34.42 mmol, 1.1 eq) was added portion wise to asolution of 20 (7.58 g, 31.29 mmol, 1 eq) in dichloromethane (150 mL)cooled to 0° C. The reaction was stirred at 0° C. for 3 h before beingpoured onto a mixture of water and ice. After 10 min stirring, thelayers were separated and the aqueous layer was extracted with ethylacetate. The combined organic layers ware washed with water and brine,dried over magnesium sulphate, filtered and concentrated to affordcompound 18 (6.78 g) as a purple oil.

Synthesis of Compound 19

C₁₆H₁₆O₃ M=244.29 g·mol⁻¹

Mass: (ESI⁺): 227.1 (M+H—H₂O)

A solution of 4-methoxyphenylmagnesium bromide (0.5M in THF, 300 mL,0.150 mol, 1.1 eq) was added drop wise under inert atmosphere to asolution of 2-methoxybenzaldehyde (18.75 g, 0.137 mol, 1 eq) in THF (188mL) cooled to 0° C. The resulting mixture was stirred at roomtemperature overnight before being poured onto a saturated aqueoussolution of NH₄Cl. The aqueous layer was extracted with ethyl acetateand the combined organic layers were dried over sodium sulphate,filtered and concentrated to afford compound 19 (37.5 g) as a brown oil.

Synthesis of Compound 20

C₁₅H₁₄O₃ M=242.27 g·mol⁻¹

Mass: (GC-MS): 51; 64; 77; 92; 107; 121; 128; 135; 139; 181; 197; 211;225; 242

Pyridinium chlorochromate (34.3 g, 159 mmol, 2 eq) was added to asolution of alcohol 19 (19.4 g, 79.4 mmol, 1 eq) in dichloromethane (210mL) containing molecular sieves. The reaction mixture was stirredovernight at room temperature, filtered to remove PCC residues andmolecular sieves and concentrated. The crude residue was purified onsilica gel chromatography (cyclohexane/ethyl acetate 100:0 to 85:15) toafford ketone 20 (12.6 g, 38% yield) as a yellowish solid.

Synthesis of Compound 21

C₁₄H₁₄O₂ M=214.26 g·mol⁻¹

Mass: (GC-MS): 214

Procedure A.

10% Pd/C was added to a solution of 18 (1.5 g, 6.6 mmol, 1 eq) inethanol. The solution was stirred under hydrogen atmosphere under 30bars until completion of the reaction. Palladium particles were removedby filtration and the solution was concentrated to afford compound 21(1.32 g, 93% yield) as a white powder.

Procedure B.

A solution of 18 (8.1 g, 35.5 mmol, 1 eq) in acetonitrile (130 mL) underinert atmosphere was cooled to 0° C. TMSCl (20.7 mL, 163.3 mmol, 4.6 eq)followed by NaBH₃CN (10.5 g, 1667 mmol, 4.7 eq) were slowly added(exothermic reaction). The resultant yellow suspension was stirred atroom temperature for 2 h before being poured onto water. Dichloromethanewas then added and the organic layer was separated, washed with brine,dried over magnesium sulphate, filtered and concentrated. The cruderesidue was purified on silica gel chromatography (cyclohexane/ethylacetate 100:0 to 83:17) to afford the target compound 21 (80% yield) asa yellowish solid.

Synthesis of Compound 22

C₄₉H₄₈O₆ M=732.90 g·mol⁻¹

Mass: (ESI⁺): 755.4 (M+Na); 771.4 (M+K)

To a solution of 17 (50 mg, 0.093 mmol, 1 eq) in toluene (0.30 mL)cooled to 0° C. under inert atmosphere were successively added 21 (30mg, 0.140 mmol, 1.5 eq), tributylphosphine (0.35 mL, 0.140 mmol, 1.5 eq)and 1,1′-(azodicarbonyl)dipiperidine (35 mg, 0.140 mmol, 1.5 eq). Thereaction mixture was stirred at 0° C. for 30 min. A dense precipitateappeared and the mixture was dissolved with dichloromethane andconcentrated under reduced pressure to give a white residue which waspurified on silica gel chromatography (cyclohexane/ethyl acetate 100:0to 80:20) to afford the target compound 22 (63 mg, 93% yield) ascolorless oil.

Synthesis of Compound 23

C₄₉H₅₀O₇ M=750.92 g·mol⁻¹

Mass: (ESI⁺): 7718 (M+Na); 789.7 (M+K)

To a cooled solution (0° C.) of 22 (62 mg, 0.085 mmol, 1 eq) inanhydrous THF (0.837 mL) was added BH₃.Me₂S (2M solution in THF, 0.169mL, 0.338 mmol, 4 eq). The resultant solution was stirred overnight atroom temperature before being cooled again to 0° C. Water (0.107 mL,23.6 mmol, 70 eq), hydrogen peroxide (30% aqueous solution, 0.258 mL,10.1 mmol, 30 eq) and sodium hydroxide (2M aqueous solution, 0.338 mL,2.7 mmol, 8 eq) were then successively added and the mixture was stirredat room temperature for 3 h. Water and ethyl acetate were added and theorganic layer was washed with brine, dried over sodium sulphate,filtered and concentrated. The crude compound was then purified onsilica gel chromatography (cyclohexane/ethyl acetate 100:0 to 75:25) toafford alcohol 23 (34 mg, 53% yield) as a white solid.

Synthesis of Compound 24

C₄₉H₄₈O₇ M=748.90 g·mol⁻¹

Mass: (ESI⁺): 771.7 (M+Na); 787.7 (M+K)

Dess Martin periodinane (29 mg, 0.068 mmol, 1.5 eq) was added to asolution of alcohol 23 (34 mg, 0.045 mmol, 1 eq) in dichloromethane(0.680 mL) cooled to 0° C. The resulting mixture was stirred at roomtemperature for 3 h before a solution of sodium hydroxide (1N aqueoussolution) and dichloromethane were added to the mixture. The organiclayer was separated, dried over sodium sulphate, filtered andconcentrated to afford the desired ketone 24 (36 mg, 70% yield) as awhite solid.

Synthesis of Compound 25

C₄₉H₄₈F₂O₆ M=770.90 g·mol⁻¹

¹⁹F NMR (CDCl₃, 282.5 MHz): −109.3 (d, J=252 Hz, 1F, CFF); −120.3 (ddd,J1=252 Hz, J2=30 Hz, J3=19 Hz, 1F, CFF).

Mass: (ESI⁺): 773.4 (M−HF); 793.5 (M+Na)

DAST (0.72 mL, 4.96 mmol, 20 eq) was added to a solution of ketone 24(183 mg, 0.244 mmol, 1 eq) in dichloromethane (0.720 mL) under inertatmosphere and the reaction mixture was stirred overnight at roomtemperature. The solution was cooled to room temperature before beingpoured in water. Dichloromethane was added and the organic layer waswashed with a saturated aqueous solution of NaHCO₃, dried over sodiumsulphate, filtered and concentrated. The crude product was purified onsilica gel chromatography (cyclohexane/ethyl acetate 100:0 to 90:10)followed by preparative HPLC (Kromasil C18, acetonitrile/water 89:11) toafford compound 25 in 32% yield as a white solid.

Synthesis of Compound 26

C₂₁H₂₄F₂O₆ M=410.41 g·mol⁻¹

¹⁹F NMR (MeOD, 282.5 MHz): −109.6 (d, J=251 Hz, 1F CFF); −122.4 (ddd,J1=251 Hz, J2=28 Hz, J3=20 Hz, 1F, CFF).

Mass: (ESI⁻): 445.2 (M+Cl)

Compound 25 (48 mg, 0.06 mmol, 1 eq) was dissolved in a mixture of THF(6.3 mL) and methanol (6.3 mL) 10% Pd/C (48 mg, 0.04 mmol, 0.7 eq)followed by 2 drops of 12N aqueous solution of hydrochloric acid wereadded. The mixture was then stirred for 1 h under hydrogen atmosphere atroom temperature before being filtered and concentrated. The crudemixture was purified on silica gel chromatography(dichloromethane/methanol 100:0 to 90:10) to afford the target compound26 (42 mg, 67% yield) as a white solid.

Synthesis of Compound 27

C₄₈H₄₆O₆ M=718.88 g·mol⁻¹

Mass: (ESI⁺): 741.8 (M+Na), 757.7 (M+K)

A solution of 17 (30 mg, 0.056 mmol, 1 eq) in toluene (0.180 mL) wascooled to 0° C. under an inert atmosphere and 4-(benzyloxy)phenol (17mg, 0.085 mmol, 1.5 eq), tributylphosphine (0.42 mL, 0.168 mmol, 3 eq)and 1,1′-(azodicarbonyl)dipiperidine (42 mg, 0.167 mmol, 3 eq) weresuccessively added. The reaction mixture was stirred at 0° C. for 30min. The reaction mixture was diluted with dichloromethane andconcentrated under reduced pressure to yield a white residue which waspurified on silica gel chromatography (cyclohexane/ethyl acetate 100:0to 80:20) to afford compound 27 (30 mg, 75% yield) as colorless oil.

Synthesis of Compound 28

C₄₈H₄₈O₇ M=736.88 g·mol⁻¹

Mass: (ESI+): 759.8 (M+Na), 775.7 (M+K)

BH₃.Me₂S (3.48 mL, 6.96 mmol, 2 eq) was added, under inert atmosphere,to a solution of 27 (1.00 g, 1.39 mmol, 1 eq) in dry tetrahydrofuran (15mL) cooled to 0° C. This mixture was stirred overnight at roomtemperature. Water (1.75 mL, 97.4 mmol, 70 eq) was then added at 0° C.,followed by a 30% aqueous solution of H₂O₂ (4.73 mL, 41.7 mmol, 30 eq)and 1M aqueous solution of sodium hydroxide (11.1 mL, 11.1 mmol, 8 eq).The resultant mixture was stirred at room temperature for 3 hours. Alarge amount of water was then added, followed by extraction with EtOAc.The organic layer was washed with brine, dried over MgSO₄, filtered andconcentrated. The crude mixture was purified by silica gelchromatography (cyclohexane/ethyl acetate 95:5 to 60:40) to afford 28(791 mg, 78% yield) as a yellowish oil.

Synthesis of Compound 29

C₄₈H₄₆O₇ M=734.87 g·mol⁻¹

Mass: (ESI⁺): 757.8 (M+Na), 773.7 (M+K)

Dess-Martin periodinane (17 mg, 0.041 mmol, 1.5 eq) was added to asolution of alcohol 28 (682 mg, 1.61 mmol, 1 eq) in dry dichloromethane(20 mL) at room temperature. The reaction was stirred overnight at roomtemperature before being diluted with dichloromethane and quenched witha 1M aqueous solution of sodium hydroxide. After extraction withdichloromethane, the organic layer was dried over MgSO₄, filtered andconcentrated to afford crude ketone 29 (730 mg, 91% yield) as ayellowish oil.

Synthesis of Compound 30

C₄₈H₄₆O₇ M=756.87 g·mol⁻¹

¹⁹F NMR (282.5 MHz): −120.6 (ddd, 1F, J1=251 Hz, J2=28 Hz, J3=20 Hz,CFF); −108.7 (d, 1F, J=251 Hz, CFF)

Mass: (ESI⁺): 779.3 [M+Na]⁺; 795.3 [M+K]⁺

A solution of ketone 29 (15 mg, 2.04 μmol, 1 eq) in DAST (0.130 mL,0.276 mmol, 130 eq) was stirred overnight under inert atmosphere at 70°C. The crude mixture was then diluted with dichloromethane and quenchedcarefully with H₂O. The organic layer was washed with a saturatedaqueous solution of NaHCO₃, dried over MgSO₄, filtered and concentrated.The crude mixture was purified by preparative TLC (cyclohexane/ethylacetate 85:15) to afford compound 30 as a yellowish oil.

Synthesis of Compound 31

C₁₃H₁₆F₂O₆ M=306.26 g·mol⁻¹

¹⁹F NMR (MeOD, 282.5 MHz): −109.2 (d, J=253 Hz, 1F, CFF); −123.0 (ddd,J1=253 Hz, J2=29 Hz, J3=20 Hz, 1F, CFF).

Mass: (ESI⁻): 341.0 [M+Cl]⁻

Compound 30 (191 mg, 0.252 mmol, 1 eq) was dissolved in a THF— ethanol(4:1, v/v, 120 mL) under inert atmosphere. 10% Pd/C (191 mg, 0.17 mmol,0.7 eq) and 9 drops of 12N aqueous solution of hydrochloric acid wereadded to the mixture which was degassed 5 times with H₂. The resultantblack suspension was stirred under an atmosphere of H₂ at roomtemperature for 45 min. The reaction mixture was filtered and thefiltrate was concentrated. The crude product was purified on silica gelchromatography (dichloromethane/Methanol 100:0 to 90:10) to afford thetarget compound 31 in 73% yield as a colorless oil.

Synthesis of Compound 32

C₁₄H₁₂O₂ M=212.24 g·mol⁻¹

Mass: (CI⁺): 213 (M+H)

4-Hydroxybenzaldehyde (4 g, 32.8 mmol, 1 eq) and potassium carbonate(4.75 g, 34.4 mmol, 1.05 eq) were dissolved in dry DMF (30 mL). Benzylbromide (4.1 mL, 34.4 mmol, 1.05 eq) was slowly added. The resultantmixture was stirred overnight under inert atmosphere at roomtemperature. Iced water was added to the reaction mixture to quench thereaction and which was then diluted with a large amount of water. Themixture was filtered and the residue was washed with water and dissolvedin ethyl acetate. The organic layer was washed with brine, dried overMgSO₄, filtered and concentrated to give quantitatively crude aldehyde32 as a yellowish oil which slowly crystallizes overtime.

Synthesis of Compound 33

C₁₄H₁₂O₂ M=21.4.26 g·mol⁻¹

Mass: (GC-MS): 91; 197; 214 (M).

A solution of aldehyde 32 (6.5 g, 30.6 mmol, 1 eq) in drytetrahydrofuran (25 mL) was added dropwise to a suspension of NaBH₄(1.51 g, 39.8 mmol, 1.3 eq) in anhydrous tetrahydrofuran (25 mL). Theresultant mixture was stirred 72 hours under inert atmosphere at roomtemperature before being quenched with iced water, diluted with diethylether, acidified with an aqueous solution of HCl 4N, and extracted withdiethyl ether. The organic layer was washed with a saturated aqueoussolution of NaHCO₃, dried over MgSO₄, filtered and concentrated to givecrude alcohol 33 (97% yield) as a white amorphous solid.

Synthesis of Compound 34

C₁₄H₁₃BrO M=277.16 g·mol⁻¹

Mass: (CI+): 107; 197, 277 (M+H)

To an ice-cold suspension of crude alcohol 33 (6 g, 28.0 mmol, 2.4 eq.)in diethyl ether (50 mL), was added. PBr₃ (1.1 mL, 11.67 mmol, 1 eq) ata rate such that the temperature did not exceed 8° C. The resultantmixture was stirred 2 hours under inert atmosphere at room temperature.The reaction mixture was then cooled in an ice-bath, quenched with icedwater and diluted with diethyl ether and ethyl acetate. The organiclayer was washed with an aqueous saturated solution of NaHCO₃, driedover MgSO₄, filtered and concentrated to give crude compound 34 (99%yield) as a white amorphous solid.

Synthesis of Compound 35

C₂₀H₂₂O₄ M=326.39 g·mol⁻¹

Mass: (ESI⁺): 349.1 (M+Na); 365.1 (M+K)

To a suspension of NaH 95% (0.61 g, 25.26 mmol, 1 eq) in dry THF (30 mL)under inert atmosphere, was added a solution ethylacetoacetate (3.5 mL,27.79 mmol, 1.1 eq) in dry THF (10 mL) The resultant mixture was stirred30 minutes at room temperature before adding dropwise a solution of 34(7 g, 25.26 mmol, 1 eq) in THF (13 mL). The mixture was then stirredovernight at 70° C. and cooled to room temperature prior to beconcentrated. The residue was taken up with Et₂O (60 mL), washed withH₂O and brine, dried over MgSO₄, filtered and concentrated. Theresultant crude mixture was purified on silica gel column (99/1 to 85/15Cyclohexane/Ethyl Acetate) to afford compound 35 (77% yield) as ayellowish oil.

Synthesis of Compound 36

C₁₈H₁₈N₂O₂ M=294.35 g·mol⁻¹

Mass: (ESI⁺): 317.1 (M+Na); 333.1 (M+K)

To a solution of 35 (6.5 g, 19.91 mmol, 1 eq) in ethanol (50 mL) wasadded hydrazine hydrate 55% (1.25 mL, 22.10 mmol, 1.1 eq) at roomtemperature. The resultant mixture was refluxed 3 hours at roomtemperature. The reaction media was then cooled in an ice bath andfiltered. The precipitate was washed with cold ethanol to affordcompound 36 (77% yield) as a white solid.

Synthesis of Compound 37

C₅₃H₅₂N₂O₆ M=812.99 g·mol⁻¹

Mass: (ESI⁺): 813.5 (M+H); 835 (M+Na); 851.4 (M+K).

Compound 36 (328 mg, 1.11 mmol, 1.5 eq) was added to a solution of 17(400 mg, 0.75 mmol, 1 eq) in dry THF (6.4 mL) under inert atmospherefollowed by tri-n-butylphosphine (198 mg, 0.98 mmol, 1.3 eq) andazodicarboxylic acid dipiperidine (376 mg, 1.49 mmol, 2.0 eq). Theresultant yellow suspension was stirred at 30° C. overnight. The solventwas removed and the crude mixture was purified on silica gelchromatography (cyclohexane/ethyl acetate 100:0 to 60:40) to affordcompound 37 (262 mg, 43% yield) as a yellowish oil.

Synthesis of Compound 38

C₅₆H₅₈N₂O₆ M=855.07 g·mol⁻¹

Mass (ESI⁺): 854.43 (M+Na); 893.5 (M+K).

Cesium carbonate (4.1 g, 12.5 mmol, 15 eq) followed by isopropyl iodide(0.99 g, 5.83 mmol, 7 eq) were added to a solution of 37 (0.68 g, 0.83mmol, 1 eq) in DMF under inert atmosphere. The resultant suspension wasstirred at room temperature for 3 h. The mixture was diluted with ethylacetate and water. The organic layer was washed with brine, dried oversodium sulphate, filtered and concentrated. The crude yellow oil waspurified on silica gel chromatography (cyclohexane/ethyl acetate 100:0to 77:23) to afford the desired compound 38 (549 mg, 77% yield) as ayellowish oil.

Synthesis of Compound 39

C₅₆H₆₀N₂O₇ M=873.08 g·mol⁻¹

Mass (ESI⁺): 873.6 (M+H); 895.6 (M+Na); 911.5 (M+K)

A solution of 9-BBN (0.5M in THF, 0.585 mL, 029 mmol, 10 eq) was addedto a solution of 38 (25 mg, 0.03 mmol, 1 eq) in dry THF, under inertatmosphere. The colorless solution was refluxed overnight before beingcooled to 0° C. Water (0.047 mL), aqueous solution of hydrogen peroxide(30% w/w, 0.100 mL) and 2N aqueous solution of sodium hydroxide (0.117mL) were successively added. The resultant white suspension was stirredfor an additional 3 h. The mixture was then diluted with ethyl acetateand poured onto water. The organic phase was then dried over magnesiumsulphate, filtered and concentrated to afford a yellowish oil.Purification over silica gel chromatography (cyclohexane/ethyl acetate100:0 to 80:20) yielded alcohol 39 (2 mg, 8% yield).

Synthesis of Compound 40

C₅₆H₅₈N₂O₇ M=871.07 g·mol⁻¹

Mass (ESI⁺): 871.6 (M+H); 893.6 (M+Na); 909.5 (M+K)

Dess-Martin periodinane (9 mg, 0.021 mmol, 1.5 eq) was added to asolution of 39 (12 mg, 0.014 mmol, 1 eq) in dry dichloromethane underinert atmosphere. The reaction mixture was stirred at room temperaturefor 2 h before being diluted with dichloromethane and 1N aqueous sodiumhydroxide. The aqueous layer was then extracted with dichloromethane andthe resultant organic layer was dried over sodium sulphate, filtered andconcentrated. The crude yellow oil was then purified on silica gelchromatography (cyclohexane/ethyl acetate 100:0 to 72:28) to affordketone 40 (8 mg, 67% yield) as a yellowish oil.

Synthesis of Compound 41

C₅₆H₅₈F₂N₂O₆ M=893.07 g·mol⁻¹

Mass (ESI⁺): 893.4 (M+H); 911.5 (M+H₂O)⁺

DAST (0.05 mL, 0.410 mmol, 45 eq) was added to a solution of 40 (8 mg,0.009 mmol, 1 eq) in dry dichloromethane (0.05 mL) under inertatmosphere. The reaction mixture was stirred at room temperatureovernight and 3 h at 35° C. The reaction mixture was allowed to reachroom temperature before being diluted with dichloromethane and pouredinto water. The organic layer was then washed with a saturated aqueoussolution of NaHCO₃, dried over magnesium sulphate, filtered andconcentrated to afford crude compound 41 as an orange residue.

Synthesis of Compound 42

C₁₀H₇FS M=178.23 g·mol⁻¹

¹⁹F NMR (CDCl₃, 282.5 MHz): −109.8 (m, 1F, Ar—F).

Mass (GC-MS): 133 (41%); 178 (100%)

Into a freshly degassed mixture of EtOH (69 mL) and H₂O (9 mL) was addedPd₂dba₃ (534 mg, 0.58 mmol, 0.025 eq), PCy₃ (660 mg, 2.35 mmol, 0.1 eq),2-thiophene boronic acid (3.00 g, 23.4 mmol, 1 eq), K₂CO₃ (6.48 g, 46.9mmol, 2 eq), and 4-bromofluorobenzene (5.17 mL, 47.0 mmol, 2 eq). Theresultant mixture was stirred overnight at 90° C. and then allowed toreach room temperature. MgSO₄ was added to quench water and the mixturewas filtered on a pad of Celite using ethyl acetate. The filtrate wasconcentrated and purified on silica gel chromatography(cyclohexane/ethyl acetate 100:0 to 95:5) to afford compound 42 (3.84 g,92% yield) as a white solid.

Synthesis of Compound 43

C₁₈H₁₂BrFOS M=375.25 g·mol⁻¹

¹⁹F NMR (CDCl₃, 282.5 MHz): −1113 (m, 1F, Ar—F).

Mass (GC-MS): 375.0 (97%); 376.0 (28%); 377.0 (100%); 416.0 (23%); 418.0(23%)

5-Bromo-2-methylbenzoic acid (725 mg, 3.37 mmol, 1 eq) was suspended indry dichloromethane (9.7 mL). Oxalyl chloride (0.32 mL, 3.74 mmol, 1.1eq) and N,N-dimethylformamide (0.013 mL, 0.17 mmol, 0.05 eq) were thenadded at room temperature and the mixture was stirred for 6 hours. Thesolvent was then evaporated to give 5-bromo-2-methylbenzoyl chloride asyellow oil. This crude product was dissolved in dry dichloromethane(19.3 mL), AlCl₃ (49.5 mg, 3.71 mmol, 1.1 eq) and 42 (600 mg, 3.37 mmol,1 eq) were then added at 0° C. (internal temperature). The resultantmixture was stirred at this temperature for 30 minutes and then at roomtemperature overnight. The reaction mixture was poured into ice andwater, the organic layer was separated and the aqueous layer wasextracted with dichloromethane. The organic layers were gathered, driedover MgSO₄, filtered and concentrated. The residue was taken up withn-hexane to form a precipitate which was collected by filtration, washedwith n-hexane and dried to afford compound 43 (69% yield) as yellowishcrystals.

Synthesis of Compound 44

C₁₈H₁₄BrFS M=361.27 g·mol⁻¹

¹⁹F NMR (CDCl₃, 282.5 MHz): −115.0 (m, 1F, Ar—F).

Mass (ESI⁺): 133 (29%); 177 (49%); 182 (55%); 184 (70%); 191 (72%); 281(39%); 360 (95%); 362 (100%)

Et₃SiH (0.99 mL, 6.18 mmol, 2.9 eq) was added at room temperature to asolution of ketone 43 (800 mg, 2.13 mmol, 1 eq) in anhydrousdichloromethane-acetonitrile (1:1, v/v, 16 mL). The resultant mixturewas cooled to 0° C. and BF₃.Et₂O (0.75 mL, 5.97 mmol, 2.8 eq) was slowlyadded. The reaction mixture was then stirred at room temperature for 3hours. A saturated aqueous solution of NaHCO₃ was slowly added at 0° C.The aqueous layer was extracted with dichloromethane and the resultantorganic layer was dried over MgSO₄, filtered and concentrated. The crudemixture was then recrystallized with MeOH to afford compound 44 (70%yield) as yellowish crystals.

Synthesis of Compound 45

C₅₃H₄₉FO₅S M=817.02 g·mol⁻¹

¹⁹F NMR(CDCl₃, 282.5 MHz): −115.2 (m, 1F, Ar—F)

Mass (ESI⁺): 839.5 [M+Na]⁺; 855.4 [M+K]⁺

n-Butyllithium (1.4M in hexanes, 0.30 mL, 0.412 mmol, 1.1 eq) was slowlyadded to a cooled solution (−70° C.) of 44 (149 mg, 0.412 mmol, 1.1 eq)in anhydrous THF-toluene (1:1, v/v, 4.8 mL) under inert atmosphere. Theresultant dark blue solution was stirred for 5 min at the sametemperature before a cooled solution (−70° C.) of cyclohexenone 8 wasslowly added. The reaction mixture was stirred for 15 min at −70° C.before being poured into water. The organic layer was then dried oversodium sulphate, filtered and concentrated to afford crude 45 (300 mg,98% yield) as yellow oil which was used in the next step without furtherpurification.

Synthesis of Compound 46

C₅₃H₄₉FO₄S M=801.02 g·mol⁻¹

¹⁹F NMR (CDCl₃, 282.5 MHz): −115.3 (m, 1F, Ar—F)

Mass (ESI⁺): 823.5 [M+Na]⁺; 839.4 [M+K]⁺

Et₃SiH (0.025 mL, 0.157 mmol, 3 eq) and BF₃.Et₂O (0.013 mL, 0.105 mmol,2 eq) were successively added to a cooled solution (−20° C.) of 45 (43mg, 0.052 mmol, 1 eq) in anhydrous dichloromethane (0.55 mL) under inertatmosphere. The resultant solution was stirred at −20° C. for 1 h 45,diluted with dichloromethane and poured into brine. The organic layerwas dried over sodium sulphate, filtered and concentrated to yield agreen oil which was then purified on silica gel chromatography(cyclohexane/ethyl acetate 100:0 to 82:18) to afford compound 46 (27 mg,64% yield) as a green oil.

Synthesis of Compound 47

C₅₃H₅₁FO₅S M=819.03 g·mol⁻¹

¹⁹F NMR (CDCl₃, 282.5 MHz): −115.3 (m, 1F, Ar—F)

Mass (ESI⁺): 841.4 [M+Na]⁺; 857.4 [M+K<]⁺

BH₃.Me₂S (2M in THF, 0.065 mL, 0.130 mmol, 4 eq) was added to a cooledsolution (0° C.) of 46 (26 mg, 0.032 mmol, 1 eq) in dry THF (0.335 mL)under inert atmosphere. The resultant solution was stirred at roomtemperature overnight before being cooled to 0° C. Water (0.041 mL, 2.27mmol, 70 eq) was then added carefully followed by hydrogen peroxide (30%w/v, 0.11 mL, 0.97 mmol, 30 eq) and 2N aqueous sodium hydroxide (0.13mL, 0.26 mmol, 8 eq). The white suspension was stirred at roomtemperature for 4 h. The reaction mixture was then diluted with ethylacetate and poured onto water. The organic layer was dried over sodiumsulphate, filtered and concentrated to yield a colorless residue whichwas then purified on silica gel chromatography (cylohexane/ethyl acetate100:0 to 77:23) to afford alcohol 47 (7 mg, 26% yield) as a yellowishresidue.

Synthesis of Compound 48

C₅₃H₄₉FO₅S M=817.02 g·mol⁻¹

¹⁹F NMR (CDCl₃, 282.5 MHz): −115.4 (m, 1F, Ar—F)

Mass (ESI⁺): 839.4[M+Na]⁺; 855.4[M+K]⁺

Dess Martin periodinane (5 mg, 0.013 mmol, 1.5 eq) was added to asolution of alcohol 47 (7 mg, 0.009 mmol, 1 eq) in dichloromethane(0.150 mL) The resultant mixture was stirred at room temperature for 1 h30 before being poured in 1N aqueous sodium hydroxide. The organic layerwas separated and the aqueous layer was extracted with dichloromethane.The combined organic layers were dried over sodium sulphate, filteredand concentrated. The crude residue was then purified on silica gelchromatography (cyclohexane/ethyl acetate 100:0 to 80:20) to affordketone 48 (6 mg, 86% yield) as a yellowish residue.

Synthesis of Compound 49

C₅₃H₄₉F₃O₄S M=839.01 g·mol⁻¹

¹⁹F NMR (CDCl₃, 282.5 MHz): −115.3 (m, 1F, Ar—F); 113.75 (dt, J1=254 Hz,J2=29 Hz, 1F, CFF); −100.4 (d, J=254 Hz, 1F, CFF).

Mass (ESI⁺): 861.3 [M+Na]⁺; 877.4 [M+K]⁺

Ketone 48 (316 mg, 0.39 mmol, 1 eq) was dissolved in DAST (1.4 mL, 11.4mmol, 30 eq) and the reaction mixture was stirred overnight under inertatmosphere at 70° C. Dichloromethane was added at room temperature andthe reaction was poured into water. The aqueous phase was extracted withdichloromethane and the organic phase was dried over Na₂SO₄, filteredand concentrated. The crude product was purified on silica gelchromatography (cyclohexane/ethyl acetate 100:0 to 78:12) followed bypreparative HPLC (Kromasil C18, MeOH/H₂O 95:5) to afford 49 (84 mg, 26%yield) as a colorless oil.

Synthesis of Compound 50

C₂₅H₂₅F₃O₄S M=478.52 g·mol⁻¹

¹⁹F NMR (CDCl₃, 282.5 MHz): −100.2 (d, J=254 Hz, 1F, CFF); −116.2 (dt,J1=254 Hz, J2=28 Hz, 1F, CFF); −117.6 (m, 1F, Ar—F).

Mass (ESI⁺): 501.2 [M+Na]⁺

Mass (ESI⁻): 513.2 [M+Cl]⁻

Compound 49 (48 mg, 0.057 mmol, 1 eq) was dissolved in THF-MeOH (1:1,v/v, 4.2 mL) under inert atmosphere. 10% Pd/C (96 mg, 0.02 mmol, 0.35eq) and 5 drops of 12N aqueous hydrochloric acid were added to themixture which was degassed 5 times with H₂. The resultant blacksuspension was stirred under an atmosphere of H₂ at room temperature for72 h. The reaction mixture was filtered over a pad of Celite 545 and thefiltrate was concentrated. The crude product was purified on silica gelchromatography (dichloromethane/Methanol 100:0 to 91:9) followed bypreparative HPLC (5-amide C18, MeCN/H₂O 38:62) to afford compound 50 in27% yield as a white solid.

Synthesis of Compound 51

C₃₅H₃₆O₅ M=536.66 g·mol⁻¹

Mass: (ESI⁺): 554.13 [M+H₂O]⁺

Under inert atmosphere, cerium chloride heptahydrate (167 mg; 0.449mmol; 1.2 eq) was added to a solution of cyclohexenone 8 (200 mg; 0.374mmol; 1 eq) in a MeOH-THF (3:1, v/v, 5 mL) cooled to −23° C. Thereaction mixture was stirred for 30 minutes at this temperature andsodium borohydride (21 mg; 0.561 mmol; 1.5 eq) was added. After afurther 45 minutes, a saturated aqueous solution of ammonium chloride(15 mL) and sodium chloride (15 mL) were added. The aqueous layer wasextracted with ethyl acetate and the combined extracts were dried oversodium sulphate, filtered and concentrated. The residue was purified bysilica gel chromatography (EtOAc/cyclohexane 3/97 to 35/65) to affordalcohol 51 (137 mg, 68% yield), as a white solid.

Synthesis of Compound 52

C₄₁H₅₀O₅Si M=650.92 g·mol⁻¹

Mass (ESI⁺): 673.5 [M+Na]⁺; 689.3 [M+K]⁺

To a solution of 51 (3.80 g; 7.09 mmol; 1 eq) in dry dimethylformamide(25 mL), under inert atmosphere, was added imidazole (1.45 g; 21.3 mmol;3 eq). The reaction mixture was stirred for 30 minutes at roomtemperature before tert-butyldimethylsilyl chloride (1.70 g; 11.3 mmol;1.6 eq) was added. The mixture was heated at 40° C. for 12 h thenquenched with water and extracted with ethyl acetate. The organic layerswere combined, washed with brine, dried over sodium sulphate, filteredand concentrated to afford compound 52 (4.57 g, 99% yield), as yellowoil. This compound was engaged in the next step without furtherpurification.

Synthesis of Compound 53

C₄₁H₅₂O₆Si M=668.93 g·mol⁻¹

Mass (ESI⁺): 691.4 [M+Na]⁺; 707.4 [M+K]⁺

To a solution of 52 (4 g; 6.15 mmol; 1 eq) in dry THF (60 mL), underinert atmosphere, was added borane-dimethylsulfide complex (12.3 mL; 2Min THF; 24.6 mmol; 4 eq) at 0° C. The reaction medium was stirredovernight at room temperature before water (7.8 mL; 0.43 mol; 70 eq),hydrogen peroxide 30% in water (21.0 mL, 0.19 mol; 30 eq) and 3M aqueoussodium hydroxide (16.4 mL; 49.2 mmol; 8 eq) were successively added at0° C. The mixture was stirred for 2 h at room temperature before beingquenched with a saturated aqueous solution of ammonium chloride (300 mL)The aqueous layer was extracted with ethyl acetate and the combinedorganic layers were washed with brine, dried over sodium sulphate,filtered and concentrated. The residue was purified on silica gelchromatography (cyclohexane/ethyl acetate) to afford alcohol 53 (754 mg,63% yield), as a yellow oil. (Crude 53 can also be engaged in the nextstep without further purification).

Synthesis of Compound 54

C₄₁H₅₀O₆Si M=666.92 g·mol⁻

Mass (ESI⁺): 689.5 [M+Na]⁺; 705.4 [M+K]⁺

To a solution of 53 (1.51 g; 2.26 mmol; 1 eq) in dry dichloromethane (23mL), under inert atmosphere, was added Dess-Martin periodinane (1.44 g;3.39 mmol; 1.5 eq) at 0° C. The mixture was stirred overnight at roomtemperature before a 1M aqueous solution of sodium hydroxide (50 mL) wasadded. The aqueous layer was extracted with dichloromethane (2×100 mL)and the combined organic layers were dried over sodium sulphate,filtered and concentrated. The residue was purified on silica gelchromatography (EtOAc/cyclohexane 1/99 to 11/89) to afford ketone 54(1.13 g, 75% yield), as yellow oil. Alternatively, ketone 54 can beobtained with 55% yield over 3 steps from 51, performing only onepurification at this last step.

Synthesis of Compound 55

C₃₅H₃₆O₆ M=552.66 g·mol⁻¹

Mass (ESI⁺): 575.3 [M+Na]⁺; 591.3 [M+K]⁺

To a solution of 54 (560 mg; 0.84 mmol) in dichloromethane (4 mL) wasadded a solution of 12N HCl in methanol (2% v/v, 4 mL). The reactionmixture was stirred overnight at room temperature. Water was then added,followed by a saturated aqueous solution of sodium hydrogen carbonateuntil neutralization. The mixture was extracted with dichloromethane,dried over sodium sulfate, filtered and concentrated. The residue wastriturated in ethanol and filtered to afford compound 55 (337 mg, 73%yield) as white solid.

Synthesis of Compound 56

Mass (ESI⁺): 617.6 [M+Na]⁺; 633.6 [M+K]⁺

To a solution of 55 (1.27 g; 2.30 mmol; 1 eq) in dry dichloromethane (3mL), under inert atmosphere, were successively added at 0° C., pyridine(0.93 mL; 11.5 mmol; 5 eq), 4-dimethylaminopyridine (60 mg; 0.46 mmol;0.2 eq) and acetic anhydride (0.44 mL; 4.60 mmol; 2 eq). The mixture wasstirred at the same temperature for 45 minutes. Water followed by 1Naqueous solution of hydrochloric acid were then added. The aqueous layerwas extracted with dichloromethane and the combined organic layers werewashed with brine, dried over sodium sulphate, filtered and concentratedto afford quantitatively ketone 56 (1.39 g) as a light yellow oil. Crude56 was engaged in the next step without further purification.

Synthesis of Compound 57

C₃₇H₃₈F₂O₆ M=616.69 g·mol⁻¹

¹⁹F NMR (CDCl₃, 282.5 MHz): −110.0 (d, J=250 Hz, 1F, CFF); −119.4 (ddd,J1=249 Hz, J2=21 Hz, J3=29 Hz, 1F, CFF).

Mass (ESI⁺): 603.4 [M−HF+Li]⁺; 619.3 [M−HF+Li]⁺; 623.3 [M+Li]⁺; 639.3[M+Na]⁺; 655.3 [M+K]⁺

To a solution of 56 (1.30 g; 2.19 mmol; 1 eq) in dry dichloromethane(5.2 mL), under inert atmosphere, was added diethylaminosulfurtrifluoride (5.2 mL; 42.4 mmol; 19 eq). The reaction medium was stirredfor 16 h at room temperature. The solution was then diluted withdichloromethane and solid sodium hydrogen carbonate was added. Themixture was stirred for additional 30 minutes at 0° C. before water wasadded dropwise. The aqueous layer was extracted with dichloromethane andthe combined organic layers were dried over sodium sulphate, filteredand concentrated. The residue was purified on silica gel chromatography(EtOAc/cyclohexane 2/98 to 12/88) to afford compound 57 (471 mg, 35%yield) in the form of a light yellow oil.

Synthesis of Compound 58

C₃₇H₄₀O₆ M=580.71 g·mol⁻¹

Mass (ESI⁺): 603.3 (M+Na)⁺; 619.3 (M+K)⁺

Under inert atmosphere, crude 51 (53.7 g) was dissolved in a mixture ofdry chloroform (500 mL) and dimethoxymethane (292 mL, 3.3 mol, 33 eq).P₂O₅ (73.9 g, 521 mmol, 5.2 eq.) was added. The reaction was kept undermechanical stirring for 1 h at room temperature. The mixture was thenfiltered on a pad of Celite® 545 (elution with dichloromethane) andwashed with a saturated aqueous solution of NaHCO₃ (700 mL) Water (1 L)was then added and the mixture was extracted with dichloromethane (2×300mL), washed with brine, dried over Na₂SO₄, filtered and concentrated toafford 58 (57.7 g) in the form of a brown oil which slowly crystallized.58 was engaged in the next step without further purification.

Synthesis of Compound 59

C₃₇H₄₂O₇ 598.73 g·mol⁻¹

Mass (ESI⁺): 621.3 (M+Na)⁺; 637.3 (M+K)⁺

Under inert atmosphere, borane-dimethyl sulfide complex (2M in THF, 199mL, 397 mmol, 4 eq) was added to a solution of 58 (57.7 g) in dry THF(497 mL) cooled to 0° C. The reaction mixture was then stirred overnightat room temperature before being cooled to 0° C. and carefully treatedwith water (125 mL, 6.96 mol, 70 eq.), followed by hydrogen peroxide(30% w/v in H₂O, 338 mL, 2.98 mol, 30 eq) and sodium hydroxide (2M inH₂O, 397 mL, 0.79 mol, 8 eq). The mixture was allowed to react for 2 hat room temperature (−25° C.) before a saturated aqueous solution ofammonium chloride (700 mL) and water (300 mL) were added to quench thereaction. The mixture was extracted with ethyl acetate (3×500 mL) andthe combined organic layers were washed with water (600 mL) and brine(600 mL), dried over Na₂SO₄, filtered, and concentrated to afford crude59 (59.5 g) in the form of a yellow oil. 59 was engaged in the next stepwithout further purification.

Synthesis of Compound 60

C₃₇H₄₀O₇ M=596.71 g·mol⁻¹

Mass (ESI⁺): 619.3 (M+Na)⁺; 635.3 (M+K)⁺

Dess-Martin periodinane (84.3 g; 199 mmol; 2 eq) was added portionwiseto a solution of crude 59 (59.5 g) in dry dichloromethane (1 L) at 0° C.The reaction was then stirred 18 h at room temperature before sodiumhydroxide (1N in H₂O, 1 L) and water (500 mL) were added. The aqueouslayer was then extracted with dichloromethane (2×400 mL) and thecombined organic layers were dried over sodium sulphate, filtered andconcentrated. The residue was purified on silica gel chromatography(cyclohexane/ethyl acetate 98:2 to 86:14, v/v on Biotage SNAP 750 gcartridge), to afford the target ketone 60 (32 g, 48% yield over 4steps) as a yellow solid.

Synthesis of Compound 61

C₃₇H₄₀F₂O₆ M=618.71 g·mol⁻¹

¹⁹F NMR (CDCl₃, 282.5 MHz): −108.5 (d, J=252 Hz, 1F, CFF); −121.0 (ddd,J1=252 Hz, J2=30 Hz, J3=20 Hz, 1F, CFF).

Mass (ESI⁺): 641.3 (M+Na)⁺; 657.3 (M+K)⁺

DAST (125 mL, 1.02 mol, 19 eq.) was slowly added to a cooled solution(0° C.) of 60 (32 g, 53.6 mmol, 1 eq.) in dry dichloromethane (145 mL)The reaction mixture was then allowed to reach room temperature and wasstirred overnight. Dichloromethane (400 mL) was then added and themixture was slowly poured into a mixture of ice (1 L), dichloromethane(300 mL) and NaHCO₃ (400 g). The mixture was vigorously stirred for 15min. Water (500 mL) was added and the aqueous layer was extracted withdichloromethane (2×300 mL). The combined organic extracts were driedover Na₂SO₄, filtered and concentrated to afford crude 61 (32.6 g) inthe form of a yellowish oil. 61 was engaged in the next step withoutfurther purification.

Synthesis of Compound 62

C₃₅H₃₆F₂O₅ M=574.65 g·mol⁻¹

¹⁹F NMR (CDCl₃, 282.5 MHz): −110.7 (d, J=249 Hz, 1F, CFF); −123.7 (ddd,J1=248 Hz, J2=29 Hz, J3=19 Hz, 1F, CFF).

Mass (ESI⁺): 577.5 [M−HF+Na]⁺; 592.5 [M+H₂O]⁺; 597.5 [M+Na]⁺; 613.5[M+K]⁺

A. To a solution of 57 (70 mg; 0.114 mmol; 1 eq) in dry methanol, underinert atmosphere, was added sodium methanolate (8 mg; 0.142 mmol; 1.25eq). The reaction medium was stirred overnight at room temperature.Water was then added followed by a 1N aqueous solution of hydrochloricacid which was added until pH=6. The mixture was extracted with ethylacetate, washed with brine, dried over sodium sulphate, filtered andconcentrated to afford alcohol 62 (65 mg) in the form of a light orangesolid, with a quantitative yield.B. Trifluoroacetic acid (98.0 mL, 1.32 mol, 25 eq.) was added to asolution of 61 (32.6 g) in dry dichloromethane (260 mL) under inertatmosphere. The reaction mixture was stirred overnight at roomtemperature. The mixture was cooled to 0° C. and water (500 mL) wasadded. The layers were separated and the organic layer was washed withwater (500 mL) The combined aqueous layers were combined and extractedwith dichloromethane (2×100 mL). The combined organic layers were washedwith sat. NaHCO₃ (250 mL), dried over sodium sulfate, filtered andconcentrated. The crude mixture was purified on silica gelchromatography (cyclohexane/ethyl acetate 98:2 to 82:18, v/v on BiotageSNAP 750 g cartridge) to afford 62 (13.6 g, 30% over 2 steps) as a whitesolid.

Synthesis of Compound 63

C₃₅H₃₆F₂O₆/C₃₅H₃₄F₂O₅ M=590.65 g·mol⁻¹/572.64 g·mol⁻¹

¹⁹F NMR (CDCl₃, 282.5 MHz):

Hydrate form: −117.3 (dd, J1=257 Hz, J2=30 Hz, 1F, CFF); −125.6 (d,J1=258 Hz, 1F, CFF).

Ketone form: −112.1 (ddd, J1=260 Hz, J2=32 Hz, J3=6 Hz, 1F, CFF); −119.4(dd, J1=260 Hz, J2=4 Hz, 1F, CFF).

Mass (ESI⁺): 608.4 [M+H₂O]⁺; 613.5 [M+Na]⁺; 619.5 [M+K]⁺

To a solution of 62 (200 mg; 0.35 mmol; eq) in dry dichloromethane,under inert atmosphere, was added Dess-Martin periodinane (295 mg; 0.70mmol; 2 eq). The reaction medium was stirred for 3 h at room temperaturebefore a 1N aqueous solution of sodium hydroxide (10 mL) was added. Theaqueous layer was extracted with dichloromethane and dried over sodiumsulphate, filtered and concentrated to afford ketone 63 (158 mg, 77%yield) as a light orange solid which rapidly evolves toward theformation of the hydrate form until equilibrium is reached.

Synthesis of Compound 64

C₅₀H₄₉ClF₂O₆ M=819.37 g·mol⁻¹

¹⁹F NMR (CDCl₃, 282.5 MHz): −112.3 (dd, J1=266 Hz, J2=27 Hz, 1F, CFF);−113.7 (dd, J1=266 Hz, J2=6 Hz, 1F, CFF).

Mass (ESI⁺): 836.7[M+H₂O]⁺; 841.8[M+Na]⁺; 857.7[M+K]⁺

In a Schlenk tube under inert atmosphere containing magnesium turnings(50 mg, 2.04 mmol, 1.2 eq) was added 2 mL (out of 5 mL) of a solution of10 (552 mg, 1.70 mmol, 1 eq) and 1,2-dibromoethane (15 μL, 0.17 mmol,0.1 eq) in dry THF (5 mL). The mixture was heated at 75° C. for 5 min toinitiate the reaction and the last 3 mL of the solution of 10 and1,2-dibromoethane were then added dropwise at room temperature. Thissolution was then stirred at 75° C. for 1 h.

2.4 mL of this Grignard solution, previously cooled to room temperature,were then added to a solution of 63 (158 mg, 0.27 mmol) in dry THF (2mL). The reaction mixture was stirred at room temperature for 2 h beforea saturated aqueous solution of ammonium chloride was added. The aqueouslayer was extracted with diethyl ether and the combined organic layerswere washed with brine, dried over sodium sulphate, filtered andconcentrated. The residue was purified on silica gel chromatography(cyclohexane/ethyl acetate 100:0 to 77:23) to afford compound 64 (152mg) as a mixture of two diastereomers with 69% yield. Thesediastereomers can be separated by semi-preparative HPLC.

Synthesis of Compound 65

C₂₂H₂₅ClF₂O₆ M=458.88 g·mol⁻¹

¹⁹F NMR (MeOD. 282.5 MHz): −114.0 (dd, J1=262 Hz, J2=7 Hz, 1F, CFF);−115.4 (dd, J1=262 Hz, J2=26 Hz, 1F, CFF).

Mass (ESI⁺): 481.3 [M+Na]⁺; 497.3 [M+K]⁺

o-Dichlorobenzene (53 μL, 0.47 mmol, 10 eq) followed by Pd/C 10% (56.0mg, 53.3 μmol, 1.1 eq) were added to a solution of 64 (38.0 mg, 46.4μmol, 1 eq) in a mixture of THF and MeOH (2:1, v/v, 26 mL) The reactionwas placed under hydrogen atmosphere and stirred at room temperature for2 h. The reaction mixture was filtered and concentrated before beingpurified on silica gel chromatography to afford the target compound 65.

Synthesis of Compound 66

C₅₀H₄₈BrClF₂O₅ M=882.27 g·mol⁻¹

¹⁹F NMR (CDCl₃, 282.5 MHz): Major anomer: −97.8 (dd, J1=246 Hz, J2=30Hz, CFF); −102.6 (d, J=246 Hz, CF).

Mass (ESI⁺): 4881.2 (M+H)⁺; 898.3 (M+H₂O)⁺.

SOBr₂ (85 μL, 1.10 mmol, 15 eq) was added at −40° C. to a solution of 65(60 mg, 0.07 mmol, 1 eq) in dry dichloromethane (0.73 mL) under inertatmosphere. The mixture was stirred while the temperature was graduallyraised to 0° C. over 5 h. Pyridine (89 μL, 1.10 mmol, 15 eq) was thenadded and the solution was stirred for an additional 1 h at 0° C. Asolution of aqueous 1M HCl was added and the solution was allowed toreach room temperature. The organic layer was collected and the aqueouslayer was extracted with dichloromethane. The combined organic layer wasthen dried over sodium sulfate, filtered and concentrated. The crudemixture was purified on silica gel chromatography (Biotage SNAP10 g,cyclohexane/ethyl acetate 100:0 to 92/8) to afford 66 (15 mg, 23%) as acolorless oil. The collected fraction contains one major isomer.

Synthesis of Compound 15

C₅₀H₄₉ClF₂O₆ M=803.37 g·mol⁻¹

¹⁹F NMR (CDCl₃, 282.5 MHz): −100.3 (d, J=254 Hz, 1F, CFF); −113.3 (td,J1=254 Hz, J2=29 Hz, 1F, CFF).

Mass: (ESI⁺): 820.00 (M+H₂O)

Bu₃SnH (7 μL, 25.5 mmol, 1.5 eq) was added to a solution of 66 (15 mg,17.0 mmol) in dry toluene (170 μL) at room temperature. The mixture wasthen heated and stirred at 110° C. for 3 h. One additional portion ofBu₃SnH (7 μL, 25.5 mmol, 1.5 eq) was then added and the mixture wasstirred at 110° C. for an additional period of 3 h. This step wasrepeated once more until no more evolution was noticed on TLC. Themixture was concentrated and purified by preparative TLC(cyclohexane/ethyl acetate 90:10, v/v) to afford 15 (2 mg, 17%, β-anomerand 4 mg contains α-anomer).

Synthesis of Compound 67

C₃₆H₃₅F₅O₇S M=706.72 g·mol⁻¹

¹⁹F NMR (CDCl₃, 282.5 MHz): −74.0 (d, J=12 Hz, CF ₃); −108.2 (dq, J1=252Hz, J2=12 Hz, CFF); −119.5 (ddd, J1=253 Hz, J2=31 Hz, J3=18 Hz, CFF).

Mass (ESI⁺): 724.3 (M+H₂O⁺); 729.2 (M+Na)⁺; 745.2 (M+K)⁺

Trifluoromethanesulfonic anhydride (9.5 mL, 57.4 mmol, 3 eq) andpyridine (4.6 mL, 57.4 mmol, 3 eq.) were added to a cooled solution (0°C.) of 62 (11.0 g, 19.1 mmol, 1 eq.) in dry dichloromethane (190 mL)under inert atmosphere. The solution was allowed to warm to roomtemperature and was stirred overnight. Water (400 mL) was then added to=the cooled mixture (0° C.) which was then extracted withdichloromethane (2×150 mL), dried over sodium sulfate, filtered andconcentrated to afford crude 67 (13.6 g) as a brown solid. 67 wasengaged in the next step without further purification.

Synthesis of Compound 68

C₄₈H₄₆F₂O₆ M=756.87 g·mol⁻¹

¹⁹F NMR (CDCl₃, 282.5 MHz): −107.9 (brd, J1=256 Hz, CFF); −110.8 (ddd,J1=257 Hz, J2=30 Hz, J3=3 Hz, CFF).

Mass (ESI⁺): 779.4 (M+Na)⁺; 795.3 (M+K)⁺

Sodium hydride (95%, 1.38 g, 57.3 mmol, 3 eq.) was added to a cooled (0°C.) solution of 4-(benzyloxy)phenol (13.4 g, 66.9 mmol, 3.5 eq.) in dryDMF (95 mL). The reaction mixture was stirred 1 h at the sametemperature before a solution of 67 (11.0 g) in dry DMF (95 mL) wasadded. The reaction mixture was stirred at 50° C. overnight before beingcooled again at 0° C. Water (250 mL) followed by a 1N aqueous solutionof sodium hydroxide (600 mL) were then added. The mixture was extractedwith diethyl ether (300 mL then 2×150 mL) and the combined organiclayers were washed with water (2×600 mL) and brine (600 mL) before beingdried over sodium sulfate, filtered and concentrated to afford crude 68(13.5 g) in the form of a purple oil. 68 was engaged in the next stepwithout further purification.

Synthesis of Compound 69

C₁₃H₁₆F₂O₆ M=306.26 g·mol⁻¹

¹⁹F NMR (D₂O, 282.5 MHz): −107.6 (brd, J=262 Hz, 1F, CFF); −111.6 (brdd,J1=262 Hz, J2=31 Hz, 1F, CFF).

Mass (ESI−): 285.1 (M−H—HF)⁻; 305.1 (M−H)⁻, 341.1 (M+Cl)⁻; 351.1(M+HCO₂)⁻

Crude 68 (13.5 g) was dissolved in a mixture of ethanol/12N HCl 4% (v/v,117 mL), tetrahydrofurane (63 mL). Palladium on activated carbon (10%,3.8 g, 0.2 eq.) was then suspended in the solution and the reactionmixture was placed under hydrogen atmosphere and stirred for 3 days atroom temperature. The reaction medium was filtered and concentratedbefore being purified on silica gel chromatography(dichloromethane/methanol 100:0 to 85:15, v/v on Biotage SNAP 340 gcartridge) to afford 69 (4.92 g, 90%) which was freeze-dried in the formof a white solid.

2. Biological Activity

a) Assay for the Facilitatory Effect on Glucose Excretion.

As experimental animal, female CD1 mice (CDM or Charles River) wereused. A test compound was dissolved in the vehicle (5% N-methylpyrrolidone, 20% PEG 400, 75% 20 mM Na₄P₂O₇ buffer, v/v/v) at theconcentration of 1 mg/mL After the body weights of the mice weremeasured and the mice randomized, the test article was orallyadministered at the dose of 1 mg/kg, 3 mg/kg and 10 mg/kg. For control,just the vehicle (5% N-methyl pyrrolidone, 20% PEG 400, 75% 20 mMNa₄P₂O₇ buffer, v/v/v) was orally administered. The oral administrationwas performed with gastric tube for mice and a 1 mL syringe. The minimumcount in one group was 3 but could reach 12 for some groups. Collectionof the urine was performed manually by gentling massaging the abdomen inorder to collect urine (3 μL) via a calibrated pipette. Urine wascollected at 1, 2, 4, 6, 8 and then 16, 18, 20, 22, 24, 26 and 28 hrs.The urine glucose concentration was measured using a WAKO glucose kit asfollows: 3 μL of urine was deposited into a 96-well micro plate forspectrometric readout. The urine aliquot was diluted with 350 μL of theWAKO working solution. For glucose concentrations that may be over therange of the WAKO glucose kit, an aliquot (35 μL) of the last solutionwas deposited into another 96-well micro plate and further diluted (10×)with 315 μL of the WAKO working solution. The absorbance of the 96-wellplates were then read at 505 nm using a BioTek SynergyMX platefluorometer/absorbance photometer and the glucose concentration wascalculated. The glucose concentrations for controls and test articles atthe different time points were averaged using Excel 2007 and plottedusing GraphPad Prism 5.

The results obtained with 16 and 50 are shown on FIGS. 1 and 2. Itappears thus that 16 (3 mg/kg) triggered a lasting glucosuria (up to 26hrs, FIG. 2).

b) Assays to Compare the Duration of Action of Compounds According tothe Invention to the One of Compounds of Prior Art by Studying theFacilitatory Effect on Glucose Excretion

The assays have been performed as described for a).

-   -   Compound 16 according to the invention has been compared to        Dapaglifozin to underline the improvement of the duration of        action, i.e. the longer duration of glucosuria, of the compound        when the intracyclic oxygen atom of the glucose moiety is        replaced by a CF₂ moiety.

This assay has been carried out at a dose of 3 mg/kg.

The results obtained are presented on FIG. 5. It appears thus that 16 (3mg/kg) triggered glucosuria that lasted beyond 24 hours compared toDapagliflozin.

-   -   Compound 16 according to the invention has been compared to the        compound 9 of WO 2009/1076550 to underline the improvement of        the duration of action of the compound when a mimic of glucose        bearing a CH—OH moiety instead of the intracyclic oxygen atom is        replaced by a mimic of glucose bearing a CF₂ in place of the        CH—OH moiety.

This assay has been carried out at a dose of 3 mg/kg.

The results obtained are presented on FIG. 6. It appears thus that 16 (3mg/kg) triggered a longer lasting glucosuria (up to 24 hrs) when nonecould be detected for the same time period for the compound 9 of WO2009/1076550.

c) Assay for the Facilitatory Effect in Decreasing Blood GlucoseExcursions Following Glucose Challenge.

As experimental animal, 18 hrs fasted female CD1 mice (CDM or CharlesRiver) were used. A test compound was dissolved in the vehicle (5%N-methyl pyrrolidone, 20% PEG 400, 75% 20 mM Na₄P₂O₇ buffer, v/v/v) atthe concentration of 1 mg/mL. After the body weights of the mice weremeasured and the mice randomized, the test article was orallyadministered at the dose of 1 mg/kg, 3 mg/kg and 10 mg/kg. For control,just the vehicle (5% N-methyl pyrrolidone, 20% PEG 400, 75% 20 mMNa₄P₂O₇ buffer, v/v/v) was orally administered. 15 min after this oraladministration, a 20% glucose solution in deionised water was orallyadministered to all mice. The oral administration was performed withgastric tube for mice and a 1 mL syringe. The minimum count in one groupwas 3 but could reach 5 for some groups. Collection of the blood wasperformed via the saphenous vein. Blood was collected at 5, 10, 30, 45,60 and 120 min post glucose challenge. One experiment consisted inadministrating the test article 18 hrs prior to a glucose challenge i.e.18 hrs post po of test article. The blood glucose concentration wasmeasured using Johnson and Johnson's OneTouch® Ultra Blood GlucoseMonitoring System. The glucose concentrations for controls and testarticles at the different time points were averaged using Excel 2007 andplotted using GraphPad Prism 5.

The results obtained with 16 are shown on FIGS. 3 and 4.

It appears thus that 16 reduced blood glucose levels in a dose-dependentmanner in normal mice following glucose challenge (FIG. 3). Moreover, 16(3 mg/kg) administered orally 18 hrs prior to glucose challenge stillreduced blood glucose excursions following glucose challenge (FIG. 4).

d) Assay to Evaluate and Compare the Stability Against Glycosidase ofCompound 26 According to the Invention to a Compound of Prior Art(Sergliflozin-A).

The enzymatic stability assay has been performed with compound 26according to the invention and compound A used as a reference compoundto control the efficacy of the β-glucosidase. The sergliflozin-Astability has also been evaluated in order to compare the improvement ofmetabolic stability obtained through the replacement of the intracyclicoxygen atom of the glucose moiety by a CF₂ moiety.

All the compounds have been treated with β-glucosidase. The stability ofcompound 26 and Sergliflozin-A has been assessed by HPLC analysis afterincubation with β-glucosidase.

A Gilson HPLC system was used, equipped with a manual injection system(V=20 μL), a Diode Array Detector (DAD172) set at a wavelength of 230 nmand a 150 mm×4.6 mm, 5 μm HICHROM Kromasil 100-5C18 reverse phasecolumn. A linear HPLC binary gradient was used as follows: solvent A waswater and solvent B was acetonitrile. Following the injection of 20 μLof a sample, solvent B was held at 20% for 3 min, increased from 20% to90% in 17 min, held at 90% for 4 min; finally, solvent B was decreasedback to 20% over 5.5 min and was held at 20% for 3.5 min.

The procedure has been adapted from J. Agric. Food Chem. 2005, 53,4918-4924.

100 μL of a solution of compound 26 at 4.5.10⁻⁴ mol·L⁻¹ in acetonitrilewas added to a solution containing 800 μL of phosphate buffer (73173Fluka, pH 7) in the presence of β-glucosidase from Almonds (10 U, 100 μLof a 5.6 mg·mL⁻¹ solution in phosphate buffer, (G4511sigma 18.7 U permg)) and was kept 4 h at 37° C.

100 μL of a solution of sergliflozin-A at 4.5.10⁻⁴ moL·L⁻¹ inacetonitrile has been treated in the presence of β-glucosidase followingthe same process.

In parallel, 100 μL of a solution of p-nitrophenyl-β-glucoside (compoundA) at 4.5.10⁻⁴ mol·L⁻¹ in phosphate buffer (73173 Fluka, pH 7) was addedto a solution containing 700 μL of phosphate buffer and 100 μL ofacetonitrile, with the presence of β-glucosidase from Almonds (10 U, 100μL of a 5.6 mg·mL⁻¹ solution in phosphatebuffer, (G4511 sigma 18.7 U permg)) and was kept 4 h at 37° C. During the process in the presence ofβ-glucosidase, a yellow coloration was observed that underlines thedecomposition of compound. A.

Sergliflozin A as referred in several publications (Discov. Med. 2011,(58): 255-263; Nature Reviews Drug Discovery 2010, 9, 551-559) is knownto undergo cleavage by β-glucosidase.

HPLC of compound 21 (FIG. 7), compound 26 (FIG. 8) and Sergliflozin-A(FIG. 10) have been performed to follow up in the experiments theformation of compound 21 (the aglycone part) implying a degradation ofthe starting material.

HPLC of compound 26 in the presence of β-glucosidase has been performed(FIG. 9) and underlines that no degradation occurs as the formation ofcompound 21 was not observed.

HPLC of Sergliflozin-A in the presence of β-glucosidase has beenperformed (FIG. 11) and underlines that degradation occurs as theformation of compound 21 was observed. In order to evaluate thepercentage of degradation, a calibration has been done on compound 21giving the following results:

Concentration g/L Area % 0.005 260 0.01 506 0.05 2962 0.1 5226

Data have been plotted (Area % versus concentration) and the linearregression obtained was characterized by the equation y=53629x and aR²=0.994.

In FIG. 11, the HPLC spectrum of Sergliflozin-A in the presence ofβ-glucosidase underlines that degradation occurs with the formation ofcompound 21 (Area %=416). The previous equation allows us to determinethat the concentration of compound 21 is 7.76.10⁻³ g/L, whichcorresponds to 3.6.10⁻⁸ mol.

This equals to 80% of degradation for Sergliflozin-A after 4 h ofincubation at 37° C. with β-glucosidase, while no degradation occurs forCompound 26 in the same condition.

e) Assay for the Inhibition of Tyrosine-Tyrosinase Reaction

Inhibition of tyrosinase, i.e. inhibition of the hydroxylation ofTyrosine into DOPA, was measured by visible spectrophotometry, and morespecifically by measuring the absorbance at 477 nm, indicative of theamount of melanine produced in vitro from the Tyrosine substrate byTyrosinase.

In order to make sure that the measured absorbance is proportional tothe enzymatic activity in the range of studied concentrations, fivestandard solutions were prepared as follows.

Standard Bis Tris milliQ Absorbance solution # Solution A bufferSolution B water QS (477 nm) 1 0 mL 2 mL 2 mL 10 mL 0.0002 2 2 mL 2 mL 2mL 10 mL 0.2626 3 4 mL 2 mL 2 mL 10 mL 0.4832 4 6 mL 2 mL 2 mL 10 mL0.5774 5 8 mL 2 mL 2 mL 10 mL 0.5447

Absorbance has been measured on a Perkin Elmer UV/Vis SpectrometerLambda 12.

Solution A (1,000 U/mL mother solution of Tyrosinase) was prepared bydissolving 40 mg of 1,250 U/mg Mushroom Tyrosinase in 1 mL 100 mM pH6.5bis Tris buffer and QS to 50 mL with milliQ water.Bis Tris buffer (100 mM pH6.5 bis Tris buffer) was prepared bydissolving 2.09 g of Bis Tris in milliQ water and QS to 100 mL.Solution B (mother solution of Tyrosine) was prepared by dissolving 100mg of Tyrosine in milliQ water and QS to 100 mL.

The standard solutions were incubated for 2 h at 37° C., then quicklycooled to 4° C. The absorbance of the solutions #2-5 was measured at 477nm against the blank solution free of Tyrosinase (solution #1). Datahave been graphed (absorbance versus Tyrosinase concentration) and thestraight line obtained, in the range of absorbance from 0 to 0.5, wascharacterized by the equation y=0.2415x−0.2343 and a R²=0.9975.

The following test solutions were prepared and their absorbance wasmeasured at 477 nm:

Solution C Solution D Solution E Description Witness SolutionHydroquinone (100% of Compound 31 (n = 5 · 10⁻⁵ Tyrosinase activity) (n= 5 · 10⁻⁵ mol) mol) Test compound 0 15.3 5.5 (mg) Solution A 1 1 1 (mL)Solution B 0.5 0.5 0.5 (mL) Bis Tris 0.5 0.5 0.5 buffer (mL) Absorbance0.4354 0.1292 0.1528 (477 nm)

With an absorbance of 0.1292, compound 31 (solution D) shows aninhibition of tyrosinase as hydroquinone (solution E).

f) Assay to Evaluate and to Compare the IC50 of Compound 31 According tothe Invention to a Compound of Prior Art (β-Arbutin).

The protocol performed is the same as in assay e.

Solution A (1,000 U/mL mother solution of Tyrosinase) was prepared bydissolving all of 50 kU Mushroom Tyrosinase in 1 mL 100 mM pH6.5 bisTris buffer and QS to 50 mL with milliQ water.

Bis Tris buffer (100 mM pH6.5 bis Tris buffer) was prepared bydissolving 2.09 g of Bis Tris in milliQ water and QS to 100 mL. pH wasadjusted at 6.5 using hydrochloric acid.

Solution B (mother solution of Tyrosine) was prepared by dissolving 20mg of Tyrosine in milliQ water and QS to 20 mL.

Stock solution of compound 31 was prepared as follow: 10 mg of compound31 was dissolved in Bis Tris buffer up to 1 ml.

Stock solution of β-arbutin was prepared as follow: 20 mg of compoundβ-arbutin was dissolved in Bis Tris buffer up to 1 ml.

The solutions were incubated for 1 h 30 at 37° C., then quickly cooledto 4° C. 100 μL of each solution were deposited on 96-well plate. Theabsorbance of the different solutions were measured at 477 nm (MolecularDevices: Spectra Max 340PC).

The different solutions were prepared as described in the differenttables below and their absorbances were reported. The absorbance ofwitness solution (without inhibitor) was set at 100% of enzymaticactivity, allowing us to determine the percentage of enzymatic activityof the different solutions.

Entry 1 Entry 2 Entry 3 Entry 4 Entry 5 Witness Solution B (μL) 50 50 5050 50 50 Solution of compound 31 (μL) 10 20 30 50 60 0 Water (μL) 240230 220 200 190 250 Solution A(μL) 30 30 30 30 30 30 Absorbance (477 nm)0.5855 0.3535 0.255 0.220 0.200 0.718 Inhibitor Concentration mg/mL 0.170.33 0.50 0.67 0.83 0.00 % activity 81.55 49.23 35.52 30.57 27.86 100.00Entry 1 Entry 2 Entry 3 Entry 4 Entry 5 Witness Solution B (μL) 50 50 5050 50 50 Solution of β-Arbutin (μL) 10 20 30 40 50 0 Water (μL) 210 200190 180 170 220 Solution A(μL) 30 30 30 30 30 30 Absorbance (477 nm)0.5010 0.3040 0.2380 0.2035 0.1970 0.722 Inhibitor Concentration mg/mL0.67 1.33 2.00 2.67 3.33 0.00 % activity 66.62 40.43 31.65 27.06 26.20100.00

Data have been plotted (% of activity versus concentration ofinhibitors) and the linear regression of the curve was used to calculatethe 1050 of both compounds. The results obtained are presented in thetable below:

Concentration Tyrosinase 100 U/mL IC50 Compound 31 0.328 mg/mL □□Arbutin 1.1 mg/mL

The results clearly underline that compound 31 is a better tyrosinaseinhibitor than β-Arbutin.

1-20. (canceled)
 21. A compound having the following formula (I):

or a pharmaceutically or cosmetically acceptable salt thereof, or atautomer or stereoisomer or a mixture of stereoisomers thereof in anyproportion, wherein: n, m and p represent, independently from oneanother, 0 or 1, R represents a hydrogen or a fluorine atom or a CH₃,CH₂F, CH₂OH, CH₂OSiR^(a)R^(b)R^(c), CH₂OR¹¹, CH₂OCOR¹¹, CH₂OCO₂R¹¹,CH₂OCONR¹²R¹³, CH₂OP(O)(OR¹⁴)₂ or CH₂OSO₃R¹⁴ group, R₁ and R₂ represent,independently from one another, a fluorine atom or an OH,OSiR^(d)R^(e)R^(f), OR¹⁵, OCOR¹⁵, OCO₂R¹⁵ or OCONR¹⁶R¹⁷ group, R₃represents a hydrogen or fluorine atom or an OH, OSiR^(g)R^(h)R^(i),OR¹⁸, OCOR¹⁸, OCO₂R¹⁸, OCONR¹⁹R²⁰, NR¹⁹R²⁰ or NR¹⁹COR¹⁸ group, R₄represents a hydrogen atom when n=1 and R₄ represents a hydrogen atom,an halogen atom or an OH, OSiR^(j)R^(k)R^(l), OR²¹, OCOR²¹, OCO₂R²¹, orOCONR²²R²³ group when n=0, or R and R₁, together with the carbon atomscarrying them, form a cyclic acetal having the following formula:

and/or (R₁ and R₂), (R₂ and R₃), and/or (R₃ and R₄), together with thecarbon atoms carrying them, form a cyclic acetal having the followingformula:

 and X₁ represents a hydrogen atom, an halogen atom, a CN, OH, SO₂,SiR^(m)R^(n)R^(o), (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,(C₃-C₇)-cycloalkyl, OR²⁴, COR²⁴, OCOR²⁴, CO₂R²⁴, NR²⁵R²⁶, NR²⁵COR²⁴,CONR²⁵R²⁶, SR²⁴, SO₂R²⁴, CSR²⁴ or OSO₃R²⁴ group, and U, V and Wrepresent, independently from one another, a phenyl, pyrazolyl,N—(C₁-C₆)alkyl-pyrazolyl, or thienyl ring, said ring being optionallysubstituted with one or more substituents selected from the groupconsisting of an halogen atom, a CN, OH, SO₂, SiR^(m)R^(n)R^(o),(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,OR²⁴, COR²⁴, OCOR²⁴, CO₂R₂₄, NR²⁵R²⁶, NR²⁵COR²⁴, CONR²⁵R²⁶, SR²⁴,SO₂R²⁴, CSR²⁴ and OSO₃R²⁴ group, wherein: R¹¹, R¹⁵, R¹⁸, R²¹ and R²⁴representing, independently from one another, a (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, 5 to 7ring-membered heterocycloalkyl, aryl, aryl-(C₁-C₆)-alkyl or(C₁-C₆)-alkyl-aryl group, this group being possibly substituted by oneor more groups chosen among an halogen atom, an OH, COOH and CHO group,R¹², R¹³, R¹⁶, R¹⁷, R¹⁹, R²⁰, R²², R²³, R²⁵ and R²⁶ representing,independently from one another, a hydrogen atom or a (C₁-C₆)-alkyl oraryl-(C₁-C₆)-alkyl group, R¹⁴ representing a hydrogen atom or a(C₁-C₆)-alkyl group, R^(a) to R^(o) representing, independently from oneanother, a (C₁-C₆)-alkyl, aryl or aryl-(C₁-C₆)-alkyl group, and R^(p) toR^(s) representing, independently from one another, a hydrogen atom or a(C₁-C₆)-alkyl group, aryl or aryl-(C₁-C₆)-alkyl group.
 22. The compoundaccording to claim 21, having the following formula (Ia), (Ib) or (Ic):


23. The compound according to claim 21, having the following formula(I-1), (I-1a), (I-1b) or (I-1c):

or a pharmaceutically or cosmetically acceptable salt thereof, atautomer, a stereoisomer or a mixture of stereoisomers in anyproportion, wherein: X₁, X₂, X₃, X₄ and X₅ represent, independently fromone another, a hydrogen atom, an halogen atom, a CN, OH, SO₂,SiR^(m)R^(n)R^(o), (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,(C₃-C₇)-cycloalkyl, OR²⁴, COR²⁴, OCOR²⁴, CO₂R²⁴, NR²⁵R²⁶, NR²⁵COR²⁴,CONR²⁵R²⁶, SR²⁴, SO₂R²⁴, CSR²⁴ or OSO₃R²⁴ group.
 24. The compoundaccording to claim 21, having the following formula (I-2), (I-2a) or(I-2b):

or a pharmaceutically or cosmetically acceptable salt thereof, or atautomer or stereoisomer or a mixture of stereoisomers thereof in anyproportion, wherein: X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈ and X₉ represent,independently from one another, a hydrogen atom, an halogen atom, a CN,OH, SO₂, SiR^(m)R^(n)R^(o), (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, OR²⁴, COR²⁴, OCOR²⁴, CO₂R²⁴,NR²⁵R²⁶, NR²⁵COR²⁴, CONR²⁵R²⁶, SR²⁴, SO₂R²⁴, CSR²⁴ or OSO₃R²⁴ group. 25.The compound according to claim 21, having the following formula (I-3),(I-3a) or (I-3b):

or a pharmaceutically or cosmetically acceptable salt thereof, or atautomer or stereoisomer or a mixture of stereoisomers thereof in anyproportion, wherein: X₁, X₂, X₃, X₄, X₅ and X₆ represent, independentlyfrom one another, a hydrogen atom, an halogen atom, a CN, OH, SO₂,Si^(m)R^(n)R^(o), (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,(C₃-C₇)-cycloalkyl, OR²⁴, COR²⁴, OCOR²⁴, CO₂R²⁴, NR²⁵R²⁶, NR²⁵COR²⁴,CONR²⁵R²⁶, SR²⁴, SO₂R²⁴, CSR²⁴ or OSO₃R²⁴ group, and X represents ahydrogen atom or a (C₁-C₆)-alkyl group.
 26. The compound according toclaim 21, having the following formula (I-4), (I-4a) or (I-4b):

or a pharmaceutically or cosmetically acceptable salt thereof, or atautomer or stereoisomer or a mixture of stereoisomers thereof in anyproportion, wherein: X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈ and X₉ represent,independently from one another, a hydrogen atom, an halogen atom, a CN,OH, SO₂, SiR^(m)R^(n)R^(o), (C₁-C₆)-alkyl, (C2-C₆)-alkenyl,(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, OR²⁴, COR²⁴, OCOR²⁴, CO₂R²⁴,NR²⁵R²⁶, NR²⁵COR²⁴, CONR²⁵R²⁶, SR²⁴, SO₂R²⁴, CSR²⁴ or OSO₃R²⁴ group. 27.The compound according to claim 21, having the following formula (I-5),(I-5a) or (I-5b):

or a pharmaceutically or cosmetically acceptable salt thereof, or atautomer or stereoisomer or a mixture of stereoisomers thereof in anyportion, wherein: X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀ and X₁₁represent, independently from one another, a hydrogen atom, an halogenatom, a CN, OH, SO₂, SiR^(m)R^(n)R^(o), (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, OR²⁴, COR²⁴, OCOR²⁴, CO₂R²⁴,NR²⁵R²⁶, NR²⁵COR²⁴, CONR²⁵R²⁶, SR²⁴, SO₂R²⁴, CSR²⁴ or OSO₃R²⁴ group. 28.The compound according to claim 21, wherein R₁, R₂ and R₃ are,independently from one another, selected from the group consisting ofOH, —O—(C₁-C₆)-alkyl, —O-aryl, —O—(C₁-C₆)-alkyl-aryl and—OCO—(C₁-C₆)-alkyl.
 29. The compound according to claim 21, wherein Rrepresents a CH₂OH, —CH₂O—(C₁-C₆)-alkyl, —CH₂O-aryl,—CH₂O—(C₁-C₆)-alkyl-aryl or —CH₇OCO—(C₁-C₆)-alkyl group.
 30. Thecompound according to claim 21, wherein R₄=H when n=1 and R₄=H or OHwhen n=0.
 31. The compound according to claim 21, wherein U, V and Wrepresent, independently from one another, a phenyl, pyrazolyl,N—(C₁-C₆)alkyl-pyrazolyl, or thienyl ring, said ring being optionallysubstituted with one or more substituents selected from the groupconsisting of an halogen atom, OH, (C₁-C₆)-alkyl, (C₂-C₆-alkenyl,(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, OR²⁴, COR²⁴, OCOR²⁴ and CO₂R²⁴, andX₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀ and X₁₁ are, independently fromone another, selected from the group consisting of a hydrogen atom, ahalogen atom, OH, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C2-C₆-alkynyl,(C₃-C₇)-cycloalkyl, OR²⁴, COR²⁴, OCOR²⁴ and CO₂R²⁴.
 32. The compoundaccording to claim 21, chosen from the following compounds:


33. A method for inhibiting a sodium-dependent glucose co-transportercomprising the administration to a person in need thereof of aneffective amount of a compound according to claim
 21. 34. The methodaccording to claim 33, wherein the sodium-dependent glucoseco-transporter is SGLT1, SGLT2 or SGLT3.
 35. A method for treating orpreventing diabetes, diabetes-related complications, hyperglycemia,hyperinsulinemia, obesity, hypertriglyceridemia, X syndrome, orarteriosclerosis, or for an anti-cancer, anti-infective, anti-viral,anti-thrombotic or anti-inflammatory treatment, comprising theadministration of an effective amount of at least one compound accordingto claim 21 to a patient in need thereof.
 36. The method according toclaim 35, wherein the method is for treating diabetes ordiabetes-related complications, and wherein the diabetes is type-IIdiabetes and the diabetes-related complications are selected from thegroup consisting of arteritis of the lower extremities, cardiacinfarction, renal insufficiency, neuropathy and blindness.
 37. A methodfor lightening, bleaching, depigmenting the skin, removing blemishesfrom the skin, or preventing pigmentation of the skin, comprising thetopical application of at least one compound according to claim
 21. 38.The method according to claim 37, wherein the blemishes of the skin areage spots or freckles.
 39. A pharmaceutical or cosmetic compositionincluding at least one compound according to claim 21 and at least onepharmaceutically or cosmetically acceptable vehicle.
 40. A process forpreparing a compound according to claim 21 wherein R₄=H, comprisingfluorination of a compound of the following formula (II):


41. A process for preparing a compound according to claim 21 for whichn=0 and R₄≠H comprising coupling of a compound of the following formula(VIII):

wherein A₁ represents —Li or —Mg-Hal, wherein Hal is a halogen atom, anda compound of the following formula (XI)

to give a compound of formula (I) according to claim 21 wherein n 0 andR₄=OH, followed optionally by substitution of the OH function to give acompound of formula (I) according to claim 21 wherein n=0 andR₄=halogen, OSiR^(j)R^(k)R^(l), OR²¹, OCOR²¹, OCO₂R²¹, or OCONR²²R²³.42. A process for preparing a compound according to claim 21 whereinR₄=H, comprising the following steps: (a4) bromination of a compound offormula (I) according to claim 21 with R₄=OH to give a compound offormula (I) according to claim 21 with R₄=Br, and (b4) reduction of thecompound of formula (I) according to claim 21 with R₄=Br obtained inprevious step (a4) to give a compound of formula (I) according to claim21 with R₄=H.
 43. A process for preparing a compound according to claim21 comprising a coupling reaction between a compound of the followingformula (XVI):

wherein R₉ represents a leaving group, with a compound of the followingformula (V):